Abstract
Background: Cellular repolarization abnormalities occur unpredictably due to disease and drug effects, and can occur even in cardiomyocytes that exhibit normal action potentials (AP) under control conditions. Variability in ion channel densities may explain differences in this susceptibility to repolarization abnormalities. Here, we quantify the importance of key ionic mechanisms determining repolarization abnormalities following ionic block in human cardiomyocytes yielding normal APs under control conditions.Methods and Results: Sixty two AP recordings from non-diseased human heart preparations were used to construct a population of human ventricular models with normal APs and a wide range of ion channel densities. Multichannel ionic block was applied to investigate susceptibility to repolarization abnormalities. IKr block was necessary for the development of repolarization abnormalities. Models that developed repolarization abnormalities over the widest range of blocks possessed low Na+/K+ pump conductance below 50% of baseline, and ICaL conductance above 70% of baseline. Furthermore, INaK made the second largest contribution to repolarizing current in control simulations and the largest contribution under 75% IKr block. Reversing intracellular Na+ overload caused by reduced INaK was not sufficient to prevent abnormalities in models with low Na+/K+ pump conductance, while returning Na+/K+ pump conductance to normal substantially reduced abnormality occurrence, indicating INaK is an important repolarization current.Conclusions: INaK is an important determinant of repolarization abnormality susceptibility in human ventricular cardiomyocytes, through its contribution to repolarization current rather than homeostasis. While we found IKr block to be necessary for repolarization abnormalities to occur, INaK decrease, as in disease, may amplify the pro-arrhythmic risk of drug-induced IKr block in humans.
Highlights
Recent evidence points toward possible large variations in ion channel densities in cardiac cells, that are modulated by environmental and intrinsic factors including: circadian rhythms (Jeyaraj et al, 2012); exposure to hormones (Odening and Koren, 2014); to drugs (Xiao et al, 2008); to sustained change in pacing rate (Qi et al, 2008); to arrhythmias (Nattel et al, 2007); and to disease (Nass et al, 2008; Michael et al, 2009)
Whereas animal studies have shown the importance of these individual mechanisms as contributors to repolarization abnormality generation under specific conditions, a quantitative understanding of the interactions and relative importance of these mechanisms in human ventricular cardiomyocytes affected by ionic current block is still missing
We focus on investigating human cardiomyocytes yielding a normal action potential (AP) under control conditions, using a population of human ventricular cardiomyocyte models (Britton et al, 2013) calibrated with experimental electrophysiological recordings
Summary
Recent evidence points toward possible large variations in ion channel densities in cardiac cells, that are modulated by environmental and intrinsic factors including: circadian rhythms (Jeyaraj et al, 2012); exposure to hormones (Odening and Koren, 2014); to drugs (Xiao et al, 2008); to sustained change in pacing rate (Qi et al, 2008); to arrhythmias (Nattel et al, 2007); and to disease (Nass et al, 2008; Michael et al, 2009). Cells have the ability to adapt to environmental factors by modulating their ion channel densities while still maintaining their physiological function, represented in cardiomyocytes by the action potential (AP). Aggressive external stimuli such as drugs or disease can sometimes challenge the stable behavior of cardiomyocytes leading to unexpected and potentially lethal abnormalities, even in tissue exhibiting apparently healthy behavior under normal conditions. Cellular repolarization abnormalities occur unpredictably due to disease and drug effects, and can occur even in cardiomyocytes that exhibit normal action potentials (AP) under control conditions. We quantify the importance of key ionic mechanisms determining repolarization abnormalities following ionic block in human cardiomyocytes yielding normal APs under control conditions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
