Such cardiac AP models have been applied to predict the effects of antiarrhythmic drugs that alter ion channel activities 35– 37 and better describe the effects of multiple ion channel inhibition than focusing purely on potency values.
A "natural" choice of cell model would be a recent physiological rabbit cell model, for example, the Mahajan et al. [ 43] cell model; however, Bishop and Plank [ 36] had to alter ion channel kinetics and tissue conductivities in order to simulate VF with this model.
The human ADLTE syndrome may therefore depend on a pathway to enhanced brain excitability different from those resulting from altered ion channels.
The critical roles of ion channels in the SAN have been demonstrated by human genetic studies in which mutations altering ion channels and their trafficking can cause SSD in patients.
Taken together, HCM iPSC-CMs exhibited altered ion channel and SR functions, consistent with previous HCM studies in animal and human cells.
Indeed, the disruption of the molecular organization, altered ion channel expression, function, location, and/or density at the AIS are emerging as key players in the pathophysiology of neurological disorders [reviewed in (Buffington and Rasband, 2011)].
The extensive construct modification altered ion channel function; peak currents were reduced, channel closure after removal of agonist was delayed, and agonist potency was increased [6], implying that the structure may not represent a native conformation, but rather an artificially stabilized, closed state.
In addition to altering ion channel flux, biophysical changes to membranes may also affect lipid raft microdomains in ways that modulate downstream signaling; an example of this phenomenon is the impact of ethanol on lipid rafts and the concomitant changes to toll like receptor 4 (TLR4) activity [ 19].
Mechanisms under discussion (Brook et al. 2004; Schulz et al., in press) include a dysfunction of the autonomic nervous system in response to direct reflexes from receptors in the lung, a cardiac malfunction due to ischemic responses in the myocardium, and/or altered ion channel functions in the myocardial cells.
