Long-Time Prediction of Arrhythmic Cardiac Action Potentials Using Recurrent Neural Networks and Reservoir Computing.

The electrical signals triggering the heart's contraction are governed by non-linear processes that can produce complex irregular activity, especially during or preceding the onset of cardiac arrhythmias. Forecasts of cardiac voltage time series in such conditions could allow new opportunities for intervention and control but would require efficient computation of highly accurate predictions. Although machine-learning (ML) approaches hold promise for delivering such results, non-linear time-series forecasting poses significant challenges. In this manuscript, we study the performance of two recurrent neural network (RNN) approaches along with echo state networks (ESNs) from the reservoir computing (RC) paradigm in predicting cardiac voltage data in terms of accuracy, efficiency, and robustness. We show that these ML time-series prediction methods can forecast synthetic and experimental cardiac action potentials for at least 15-20 beats with a high degree of accuracy, with ESNs typically two orders of magnitude faster than RNN approaches for the same network size.

Defibrillate You Later, Alligator: Q10 Scaling and Refractoriness Keeps Alligators from Fibrillation.

Effective cardiac contraction during each heartbeat relies on the coordination of an electrical wave of excitation propagating across the heart. Dynamically induced heterogeneous wave propagation may fracture and initiate reentry-based cardiac arrhythmias, during which fast-rotating electrical waves lead to repeated self-excitation that compromises cardiac function and potentially results in sudden cardiac death. Species which function effectively over a large range of heart temperatures must balance the many interacting, temperature-sensitive biochemical processes to maintain normal wave propagation at all temperatures. To investigate how these species avoid dangerous states across temperatures, we optically mapped the electrical activity across the surfaces of alligator (Alligator mississippiensis) hearts at 23°C and 38°C over a range of physiological heart rates and compare them with that of rabbits (Oryctolagus cuniculus). We find that unlike rabbits, alligators show minimal changes in wave parameters (action potential duration and conduction velocity) which complement each other to retain similar electrophysiological wavelengths across temperatures and pacing frequencies. The cardiac electrophysiology of rabbits accommodates the high heart rates necessary to sustain an active and endothermic metabolism at the cost of increased risk of cardiac arrhythmia and critical vulnerability to temperature changes, whereas that of alligators allows for effective function over a range of heart temperatures without risk of cardiac electrical arrhythmias such as fibrillation, but is restricted to low heart rates. Synopsis La contracción cardíaca efectiva durante cada latido del corazón depende de la coordinación de una onda eléctrica de excitación que se propaga a través del corazón. Heterogéidades inducidas dinámicamente por ondas de propagación pueden resultar en fracturas de las ondas e iniciar arritmias cardíacas basadas en ondas de reingreso, durante las cuales ondas espirales eléctricas de rotación rápida producen una autoexcitación repetida que afecta la función cardíaca y pude resultar en muerte súbita cardíaca. Las especies que funcionan eficazmente en una amplia gama de temperaturas cardíacas deben equilibrar los varios procesos bioquímicos que interactúan, sensibles a la temperatura para mantener la propagación normal de ondas a todas las temperaturas. Para investigar cómo estas especies evitan los estados peligrosos a través de las temperaturas, mapeamos ópticamente la actividad eléctrica a través de las superficies de los corazones de caimanes (Alligator mississippiensis) a 23°C and 38°C sobre un rango de frecuencias fisiológicas del corazón y comparamos con el de los conejos (Oryctolagus cuniculus). Encontramos que a diferencia de los conejos, los caimanes muestran cambios mínimos en los parámetros de onda (duración potencial de acción y velocidad de conducción) que se complementan entre sí para retener longitudes de onda electrofisiológicas similares a través de los rangos de temperaturas y frecuencias de ritmo. La electrofisiología cardíaca de los conejos acomoda las altas frecuencias cardíacas necesarias para mantener un metabolismo activo y endotérmico a costa de un mayor riesgo de arritmia cardíaca y vulnerabilidad crítica a los cambios de temperatura, mientras que la de los caimanes permite un funcionamiento eficaz en una serie de temperaturas cardíacas sin riesgo de arritmias eléctricas cardíacas como la fibrilación, pero está restringida a bajas frecuencias cardíacas.

Quantifying Distributions of Parameters for Cardiac Action Potential Models Using the Hamiltonian Monte Carlo Method.

Aims: Cardiac action potential (AP) models are typically given with a single set of parameter values; however, this approach does not consider variability and uncertainty across individuals and experimental conditions. As an alternative to single-value parameter fitting, we sought to use a Bayesian approach, the Hamiltonian Monte Carlo (HMC) algorithm, to find distributions of physiological parameter values for cardiac AP models across a range of cycle lengths (CLs) and dynamics. Methods: To assess HMC's accuracy for cardiac data, we applied it to synthetic APs from the Mitchell-Shaeffer (MS) and Fenton-Karma (FK) models with added noise over a range of physiological CLs, some of which included alternans. To show the applicability of HMC to experimental data, we calculated parameter distributions for both models using micro-electrode recordings of zebrafish APs from a range of CLs. Results: For synthetic APs generated from three CLs using the MS (FK) models, HMC produced unimodal quasi-symmetric distributions for all five (13) parameters. APs generated by setting all parameters in the MS (FK) model to the modes of their corresponding marginal distributions yielded errors in voltage traces below 5.0% (0.6%). We also obtained distributions for the MS (FK) model parameters using zebrafish data to construct the first minimal model of the zebrafish AP, with voltage trace errors below 4.8% (3.4%). Conclusion: We have shown that HMC can identify not only a single set of parameter values but also viable distributions for cardiac AP model parameters using synthetic and experimental data. Because HMC generates samples from the parameter distributions based on input data, it can produce families of parameterizations that can be used in population-based modeling approaches without the need for rejecting a large number of randomly generated candidate parameterizations. HMC also has the potential to provide quantitative measures of spatial/individual variability and uncertainty.

Generation of Monophasic Action Potentials and Intermediate Forms.

The monophasic action potential (MAP) is a near replica of the transmembrane potential recorded when an electrode is pushed firmly against cardiac tissue. Despite its many practical uses, the mechanism of MAP signal generation and the reason it is so different from unipolar recordings are not completely known and are a matter of controversy. In this work, we describe a method to simulate realistic MAP and intermediate forms, which are multiphasic electrograms different from an ideal MAP. The key ideas of our method are the formation of compressed zones and junctional spaces-regions of the extracellular and bath or blood pool directly in contact with electrodes that exhibit a pressure-induced reduction in electrical conductivity-and the presence of a complex network of passive components that acts as a high-pass filter to distort and attenuate the signal that reaches the recording amplifier. The network is formed by the interaction between the passive tissue properties and the double-layer capacitance of electrodes. The MAP and intermediate forms reside on a continuum of signals, which can be generated by the change of the model parameters. Our model helps to decipher the mechanisms of signal generation and can lead to a better design for electrodes, recording amplifiers, and experimental setups.

Fatal arrhythmias: Another reason why doctors remain cautious about chloroquine/hydroxychloroquine for treating COVID-19.

BACKGROUND: Early during the current coronavirus disease 19 (COVID-19) pandemic, hydroxychloroquine (HCQ) received a significant amount of attention as a potential antiviral treatment, such that it became one of the most commonly prescribed medications for COVID-19 patients. However, not only has the effectiveness of HCQ remained questionable, but mainly based on preclinical and a few small clinical studies, HCQ is known to be potentially arrhythmogenic, especially as a result of QT prolongation. OBJECTIVE: The purpose of this study was to investigate the arrhythmic effects of HCQ, as the heightened risk is especially relevant to COVID-19 patients, who are at higher risk for cardiac complications and arrhythmias at baseline. METHODS: An optical mapping technique utilizing voltage-sensitive fluorescent dyes was used to determine the arrhythmic effects of HCQ in ex vivo guinea pig and rabbit hearts perfused with the upper therapeutic serum dose of HCQ (1000 ng/mL). RESULTS: HCQ markedly increased action potential dispersion, resulted in development of repolarization alternans, and initiated polymorphic ventricular tachycardia. CONCLUSION: The study results further highlight the proarrhythmic effects of HCQ.

Engineered Cardiac Pacemaker Nodes Created by TBX18 Gene Transfer Overcome Source-Sink Mismatch.

Every heartbeat originates from a tiny tissue in the heart called the sinoatrial node (SAN). The SAN harbors only ≈10 000 cardiac pacemaker cells, initiating an electrical impulse that captures the entire heart, consisting of billions of cardiomyocytes for each cardiac contraction. How these rare cardiac pacemaker cells (the electrical source) can overcome the electrically hyperpolarizing and quiescent myocardium (the electrical sink) is incompletely understood. Due to the scarcity of native pacemaker cells, this concept of source-sink mismatch cannot be tested directly with live cardiac tissue constructs. By exploiting TBX18 induced pacemaker cells by somatic gene transfer, 3D cardiac pacemaker spheroids can be tissue-engineered. The TBX18 induced pacemakers (sphTBX18) pace autonomously and drive the contraction of neighboring myocardium in vitro. TBX18 spheroids demonstrate the need for reduced electrical coupling and physical separation from the neighboring ventricular myocytes, successfully recapitulating a key design principle of the native SAN. ß-Adrenergic stimulation as well as electrical uncoupling significantly increase sphTBX18s' ability to pace-and-drive the neighboring myocardium. This model represents the first platform to test design principles of the SAN for mechanistic understanding and to better engineer biological pacemakers for therapeutic translation.

Theoretical Modeling and Experimental Detection of the Extracellular Phasic Impedance Modulation in Rabbit Hearts.

Theoretical cardiac electrophysiology focuses on the dynamics of the membrane and sarcoplasmic reticulum ion currents; however, passive (e.g., membrane capacitance) and quasi-active (response to small signals) properties of the cardiac sarcolemma, which are quantified by impedance, are also important in determining the behavior of cardiac tissue. Theoretically, impedance varies in the different phases of a cardiac cycle. Our goal in this study was to numerically predict and experimentally validate these phasic changes. We calculated the expected impedance signal using analytic methods (for generic ionic models) and numerical computation (for a rabbit ventricular ionic model). Cardiac impedance is dependent on the phase of the action potential, with multiple deflections caused by a sequential activation and inactivation of various membrane channels. The two main channels shaping the impedance signal are the sodium channel causing a sharp and transient drop at the onset of action potential and the inward rectifying potassium channel causing an increase in impedance during the plateau phase. This dip and dome pattern was confirmed in an ex-vivo rabbit heart model using high-frequency sampling through a monophasic action potential electrode. The hearts were immobilized using a myosin-inhibitor to minimize motion artifacts. We observed phasic impedance changes in three out of four hearts with a dome amplitude of 2 - 4Ω. Measurement of phasic impedance modulation using an extracellular electrode is feasible and provides a non-invasive way to gain insight into the state of cardiac cells and membrane ionic channels. The observed impedance recordings are consistent with the dip and dome pattern predicted analytically.

Mechanism for Amplitude Alternans in Electrocardiograms and the Initiation of Spatiotemporal Chaos.

It is widely believed that one major life-threatening transition to chaotic fibrillation occurs via spiral-wave breakup that is preceded by spatiotemporal dispersion of refractoriness due to alternations in the duration of the cardiac action potential (AP). However, recent clinical and experimental evidence suggests that other characteristics of the AP may contribute to, and perhaps drive, this dangerous dynamical instability. To identify the relative roles of AP characteristics, we performed experiments in rabbit hearts under conditions to minimize AP duration dynamics which unmasked pronounced AP amplitude alternans just before the onset of fibrillation. We used a simplified ionic cell model to derive a return map and a stability condition that elucidates a novel underlying mechanism for AP alternans and spiral breakup. We found that inactivation of the sodium current is key to developing amplitude alternans and is directly connected to conduction block and initiation of arrhythmias. Simulations in 2D where AP amplitude alternation led to turbulence confirm our hypothesis.

Simulation-Based Approaches for Determining Membrane Permeability of Small Compounds.

Predicting the rate of nonfacilitated permeation of solutes across lipid bilayers is important to drug design, toxicology, and signaling. These rates can be estimated using molecular dynamics simulations combined with the inhomogeneous solubility-diffusion model, which requires calculation of the potential of mean force and position-dependent diffusivity of the solute along the transmembrane axis. In this paper, we assess the efficiency and accuracy of several methods for the calculation of the permeability of a model DMPC bilayer to urea, benzoic acid, and codeine. We compare umbrella sampling, replica exchange umbrella sampling, adaptive biasing force, and multiple-walker adaptive biasing force for the calculation of the transmembrane PMF. No definitive advantage for any of these methods in their ability to predict the membrane permeability coefficient Pm was found, provided that a sufficiently long equilibration is performed. For diffusivities, a Bayesian inference method was compared to a generalized Langevin method, both being sensitive to chosen parameters and the slow relaxation of membrane defects. Agreement within 1.5 log units of the computed Pm with experiment is found for all permeants and methods. Remaining discrepancies can likely be attributed to limitations of the force field as well as slowly relaxing collective movements within the lipid environment. Numerical calculations based on model profiles show that Pm can be reliably estimated from only a few data points, leading to recommendations for calculating Pm from simulations.

Accelerating the use of molecular modeling in the high school classroom with VMD Lite.

It is often difficult for students to develop an intuition about molecular processes, which occur in a realm far different from day-to-day life. For example, thermal fluctuations take on hurricane-like proportions at the molecular scale. Students need a way to visualize realistic depictions of molecular processes to appreciate them. To this end, we have developed a simplified graphical interface to the widely used molecular visualization and analysis tool Visual Molecular Dynamics (VMD) called VMD lite. We demonstrate the use of VMD lite through a module on diffusion and the hydrophobic effect as they relate to membrane formation. Trajectories from molecular dynamics simulations, which students can interact with freely, illustrate the dynamical behavior of lipid molecules and water. VMD lite was tested by ∼70 students with overall positive reception. Remaining deficiencies in conceptual understanding were noted, however, and the module has been revised in response.

Electrocardiogram reconstruction from high resolution voltage optical mapping.

Electrocardiogram recordings during opucal mapping experiments in heart tissue are commonly used tu monitor the health of the preparation and to obtain dominant frequencies during arrhythmic and defibrillatory studies. However the use of ECG reconstructed from optical mapping is seldom used and to date it has not been strictly validated. In this manuscript we present the first detailed validation and comparison of Optical Mapping ECG, or OM-ECG, with standard ECG recordings by calculating the electrostatic potential in space as a function of the voltage measured optically and describe the different approximations that can be used to obtain unipolar or bipolar ECG recordings. We found that in small/medium hearts, such as rabbits, leads that are aligned apex to base only require activation recording from one surface (anterior or posterior) for the OM-ECG to match the ECG while leads aligned left to right may require both an anterior and posterior optical mapping recording. The discrepancy between leads is due to symmetries in the ventricular activations. In the case of ischemic hearts where activations even-out more, the match between the OM-ECG and standard ECG may require only one surface recording for both left-right and base-apex leads. We believe that this methodology has two main and direct applications in the study of cardiac dynamics. The first is during studies of defibrillation where information after the shock may be crucial in the development of new strategies, OM-ECGs do not suffer the current artifacts of standard ECGs during shocks and can be calculated during the entire activation. We present examples in rabbit ventricles where even low amplitude pacing artifacts are captured by the ECG but do not appear in the OM-ECG. The second use of this technique is for reconstructions of intramural dynamics in larger hearts where differences between the ECG and OM-ECG obtained from anterior and posterior recordings can be used to derive the intramural activation.