In Vivo and In Silico Investigation into Mechanisms of Frequency Dependence of Repolarization Alternans in Human Ventricular Cardiomyocytes
Rationale: Repolarization alternans (RA) are associated with arrhythmogenesis. Animal studies have revealed potential mechanisms, but human-focused studies are needed. RA generation and frequency dependence may be determined by cell-to-cell variability in protein expression, which is regulated by genetic and external factors.
Objective: To characterize in vivo RA in human, and to investigate in silico using human models the ionic mechanisms underlying the frequency-dependent differences in RA behaviour identified in vivo.
Methods and Results: In vivo electrograms were acquired at 240 sites covering the epicardium of 41 patients at 6 cycle lengths (600-350ms). In silico investigations were conducted using a population of biophysically-detailed human models incorporating variability in protein expression and calibrated using in vivo recordings. Both in silico and in vivo, two types of RA were identified, with Fork and Eye-type restitution curves, based on RA persistence or disappearance, respectively, at fast pacing rates. In silico simulations show RA are strongly correlated with fluctuations in sarcoplasmic reticulum (SR) calcium, due to strong release and weak reuptake. Large L-type calcium current (ICaL) conductance is responsible for RA disappearance at fast frequencies in Eye-type (30% larger in Eye-type vs Fork-type, p<0.01), due to SERCA potentiation caused by frequency-induced increase in intracellular calcium. Large INaCa is the main driver in translating Ca2+ fluctuations into RA.
Conclusions: In human in vivo and in silico, two types of RA are identified, with RA persistence/disappearance as frequency increases. In silico, ICaL and INaCa determine RA human cell-to-cell differences through intracellular and SR Calcium regulation.
- Received October 15, 2015.
- Revision received November 18, 2015.
- Accepted November 24, 2015.
Circulation Research is published on behalf of the American Heart Association, Inc., by Wolters Kluwer. This is an open access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits use, distribution, and reproduction in any medium, provided that the original work is properly cited.