Simultaneous Quantification of Spatially Discordant Alternans in Voltage and Intracellular Calcium in Langendorff-Perfused Rabbit Hearts and Inconsistencies with Models of Cardiac Action Potentials and Ca Transients.

Daniel Hornung,Johannes Schröder-Scheteling,Flavio H Fenton,Yanyan C Ji,Stefan Luther,Ilija Uzelac,Elizabeth M Cherry,Richard A Gray

doi:10.3389/fphys.2017.00819

Abstract

Rationale: Discordant alternans, a phenomenon in which the action potential duration (APDs) and/or intracellular calcium transient durations (CaDs) in different spatial regions of cardiac tissue are out of phase, present a dynamical instability for complex spatial dispersion that can be associated with long-QT syndrome (LQTS) and the initiation of reentrant arrhythmias. Because the use of numerical simulations to investigate arrhythmic effects, such as acquired LQTS by drugs is beginning to be studied by the FDA, it is crucial to validate mathematical models that may be used during this process.Objective: In this study, we characterized with high spatio-temporal resolution the development of discordant alternans patterns in transmembrane voltage (Vm) and intracellular calcium concentration ([Cai]+2) as a function of pacing period in rabbit hearts. Then we compared the dynamics to that of the latest state-of-the-art model for ventricular action potentials and calcium transients to better understand the underlying mechanisms of discordant alternans and compared the experimental data to the mathematical models representing Vm and [Cai]+2 dynamics.Methods and Results: We performed simultaneous dual optical mapping imaging of Vm and [Cai]+2 in Langendorff-perfused rabbit hearts with higher spatial resolutions compared with previous studies. The rabbit hearts developed discordant alternans through decreased pacing period protocols and we quantified the presence of multiple nodal points along the direction of wave propagation, both in APD and CaD, and compared these findings with results from theoretical models. In experiments, the nodal lines of CaD alternans have a steeper slope than those of APD alternans, but not as steep as predicted by numerical simulations in rabbit models. We further quantified several additional discrepancies between models and experiments.Conclusions: Alternans in CaD have nodal lines that are about an order of magnitude steeper compared to those of APD alternans. Current action potential models lack the necessary coupling between voltage and calcium compared to experiments and fail to reproduce some key dynamics such as, voltage amplitude alternans, smooth development of calcium alternans in time, conduction velocity and the steepness of the nodal lines of APD and CaD.

Highlights

Long-QT syndrome (LQTS), characterized by abnormal prolongation of the QT interval (Schwartz et al, 1993), is a result of delayed repolarizations in the heart and can increase the risk of life-threatening arrhythmias, with a mortality rate of 20% within the first year after first detection and up to 50% in the 10 years for untreated patients (Schwartz, 1985)
LQTS is usually accompanied by T-wave alternans (Zareba et al, 1994) where the duration of the T wave can vary from one beat to the (Jayakrishnan and Krishnakumar, 2006)
We found the ability to reach faster pacing rates without inducing fibrillation was highly correlated with uniform physiological temperature across the entire heart and with smaller pacing cycle length (PCL) steps, especially when the PCL was less than 160 ms

Summary

Introduction

Long-QT syndrome (LQTS), characterized by abnormal prolongation of the QT interval (Schwartz et al, 1993), is a result of delayed repolarizations in the heart and can increase the risk of life-threatening arrhythmias, with a mortality rate of 20% within the first year after first detection and up to 50% in the 10 years for untreated patients (Schwartz, 1985). LQTS is usually accompanied by T-wave alternans (Zareba et al, 1994) where the duration of the T wave can vary from one beat to the (Jayakrishnan and Krishnakumar, 2006). This long-short alternation in duration and in some cases amplitude has been shown to arise from a period-doubling bifurcation (Nolasco and Dahlen, 1968; Guevara et al, 1984) originating at the cellular level (Pastore et al, 1999). Alternans can lead to complex spatiotemporal patterns along the epicardium and endocardium (Gizzi et al, 2013) and eventually to conduction block and fibrillation (Fenton et al, 2002; Choi et al, 2007)

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