Table 1.

Methods used to evaluate cardiac arrhythmia in heart failure.

Approach	Method	Description	Invasiveness	Advantages	Limitations
In vivo	Electrocardiogram (ECG)	Measuring voltage versus time from electrodes placed on the skin	Non-invasive	Easy to perform Can be used to detect most sustained arrhythmias	Provides limited information on mechanism of arrhythmia Struggles to detect intermittent arrhythmias
In vivo	Echocardiography	Using sound waves to facilitate live imaging of the heart. This can be used to indirectly estimate measurements of the cardiac cycle	Non-invasive	Provides detailed structural information on the heart Relatively easy to perform	Cardiac cycle is estimated High interobserver variability
Ex vivo	Monophasic and transmembrane action potentials	The recording of action potentials from either a single or group of cardiomyocytes using intracellular and extracellular electrodes	Invasive/Non-invasive	Direct recoding of transmembrane voltage changes Can be recorded in freely beating heart/preparations Ideally suited for arrhythmia induction and testing	Low spatial resolution Direct electrode contact can damage tissue Hearts/tissue samples often require preparation, e.g., Langendorff perfusion
Ex vivo	Voltage and calcium optical mapping	Using voltage and/or calcium-sensitive dyes to analyse action potential propagation and calcium transients	Partially invasive	High spatial resolution allows visualisation of propagation patterns present in complex arrhythmias Enables the electrophysiological assessment of samples following electrical shocks which may be elicited to induce arrhythmogenesis or mimic defibrillation	Hearts/tissue samples often require preparation, e.g., Langendorff perfusion Motion artefacts can occur if samples are uncoupled High skill level required Dye toxicity and photobleaching
Ex vivo/In vitro	Patch clamping	Microelectrodes are used to interrogate membrane potential and ion current channel function in excitable cardiac cells and preparations	Invasive	Enables electrophysiological characterisation of a subset of individual ion channel(s) (voltage clamp) Enables the direct recording of action potentials (current clamp) Enables the comprehensive characterisation of electrophysiological events at a single-cell level under controlled conditions	High skill level required Cannot detect electrophysiological events related to re-entry Low throughput
In vitro	Multi-electrode arrays (MEA)	A surface containing embedded electrodes acts as a neural interface to assay the electrical activity of cultured cells	Non-invasive	High-throughput multiplexed reads Relatively unharmful to the cells, allowing experiments to be performed over a long period of time	Low spatial resolution An extracellular field potential is recorded rather than the action potential itself
In vitro	Intracellular calcium imaging	A fluorescent calcium indicator is either added to the cells or endogenously expressed to visualise calcium transients	Partially invasive	High spatial resolution allows assessment of intracellular calcium handling Can be performed in conjunction with voltage-sensitive dyes	Dyes can be toxic to the cells Skill required to determine the appropriate indicator/dye for imaging
In silico	Human-based computational models and simulations	Simulations using mathematical models of human cardiac pathophysiology yield high spatio-temporal resolution data, including time course of ionic currents, action potentials, calcium transients, conduction velocity and the ECG.	Non-invasive	Fast and cost-effective way of evaluating arrhythmias Can be used to generate predictions on arrhythmia mechanisms which would be imperceptible using solely experimental data	Can be reliant on experimental data Computational power is limited requiring researchers to balance the complexity of their model against its performance