Dynamic Clamp

Abstract

M utations in KCNH2 (hERG) underlie the long-QT2 syndrome. Most long-QT2 mutations produce a trafficking defect resulting in a decrease in n, the number of functional channels on the cell surface. Some mutations can also alter gating characteristics. The short-QT syndrome generally relates to shifts in the voltage dependence of inactivation to more depolarized potentials results in less inward rectification at physiological potentials and a larger time-dependent current at the expense of the magnitude of the repolarizing tail current. Article see p 1265Altomare et al 1 provide conceptual advances in understanding the relative contributions of changes in gating features and gmax to action potential duration (APD) and its temporal variance. They should be congratulated for their innovative experimental approach and the interesting results. The insights that they provide seem to have clinical relevance.Altomare et al 1 substituted the innate guinea pig rectifier K + current (I Kr ) with injection of a modeled and programmable I Kr . This approach allows an assessment of the impact of programmable changes in the characteristics of I Kr on temporal variance on APD in the context of an otherwise native guinea pig cardiac action potential. This also allows requisite changes in cycle length elicited by a command potential in action potential clamp mode.They examined temporal variability in repolarization. 1Poincare plots allowed an assessment of the dynamics of the beat-to-beat variability of APD. Two metrics of beat-to-beat variability were computed: (1) SD1, the mean orthogonal deviation from the line of identity in the Poincare plot comparing the APD of beat n+1 with the APD of the nth beat; (2) SD2 is another metric of mean of the deviations from the identity line. However, the SD1/SD2 ratio provides a description of frequency component of the beat-to-beat variability being manifest as an alternans pattern versus a more complex pattern occurring over a longer period of time.Poincare was a brilliant French mathematical physicist born in 1854. He made important contributions to celestial physics and probability theorems. He was genuinely interested in the fundamental laws that govern behavior of complex systems, over time. We build on the shoulders of such multidisciplinary work that might not be originally construed as being relevant to human biology. His work is an example of how inquisitive science can have unexpected and impactful applications.There are many fascinating results from the work of Altomare et al.1 First, the command injection of the modeled innate I Kr fully restored the SD1 metric of beat-to-beat variability to control values, but did not restore the SD1/SD2 ratio. Thus, the command modeled I Kr failed to fully substitute for the native I Kr during longer epochs. This suggests that there is an intrinsic control mechanism manifest in native I Kr during longer periods of data acquisition that is not fully realized in the single snap-shot measurement of I Kr . The implication is that there are other co...