Late sodium current block for drug-induced long QT syndrome: Results from a prospective clinical trial.

Drug-induced long QT syndrome has resulted in many drugs being withdrawn from the market. At the same time, the current regulatory paradigm for screening new drugs causing long QT syndrome is preventing drugs from reaching the market, sometimes inappropriately. In this study, we report the results of a first-of-a-kind clinical trial studying late sodium (mexiletine and lidocaine) and calcium (diltiazem) current blocking drugs to counteract the effects of hERG potassium channel blocking drugs (dofetilide and moxifloxacin). We demonstrate that both mexiletine and lidocaine substantially reduce heart-rate corrected QT (QTc) prolongation from dofetilide by 20 ms. Furthermore, all QTc shortening occurs in the heart-rate corrected J-Tpeak (J-Tpeak c) interval, the biomarker we identified as a sign of late sodium current block. This clinical trial demonstrates that late sodium blocking drugs can substantially reduce QTc prolongation from hERG potassium channel block and assessment of J-Tpeak c may add value beyond only assessing QTc.

Fluctuation analysis of mitochondrial NADH fluorescence signals in confocal and two-photon microscopy images of living cardiac myocytes.

A fluctuation analysis was performed on the reduced nicotine adenine dinucleotide (NADH) fluorescence signal from resting rabbit myocytes using confocal and two-photon microscopy. The purpose of this study was to establish whether any co-ordinated biochemical processes, such as binding, metabolism and inner mitochondrial membrane potential, were contributing to NADH signal fluctuations above background instrument noise. After a basic characterization of the instrument noise, time series of cellular NADH fluorescence images were collected and compared with an internal standard composed of NADH in the bathing medium. The coefficient of variation as a function of mean signal amplitude of cellular NADH fluorescence and bathing media NADH was identical even as a function of temperature. These data suggest that the fluctuations in cellular NADH fluorescence in resting myocytes are dominated by sampling noise of these instruments and not significantly modified by biological processes. Further analysis revealed no significant spatial correlations within the cell, and Fourier analysis revealed no coherent frequency information. These data suggest that the impact of biochemical processes, which might affect cellular NADH fluorescence emission, are either too small in magnitude, occurring in the wrong temporal scale or too highly spatially localized for detection using these standard optical microscopy approaches.