scholarly journals Realization of fully biological restoration of cardiac rhythm: a computational translational exploration

2021 ◽  
Vol 42 (Supplement_1) ◽  
Author(s):  
T De Coster ◽  
B Ordog ◽  
A A F De Vries ◽  
A V Panfilov ◽  
D A Pijnappels
Keyword(s):  
Gene Therapy ◽  
Ion Channels ◽  
Cardiac Rhythm ◽  
Spiral Wave ◽  
Local Delivery ◽  
Spiral Waves ◽  
Point Of View ◽  
Dependent Manner ◽  
Systemic Delivery ◽  
Public Grant

Abstract Background Recently it was demonstrated how the heart itself could be enabled to quickly restore its rhythm by realizing a biologically-integrated cardiac defibrillator (BioICD) through modification and subsequent expression of ion channels in cardiomyocytes [1]. By incorporating these frequency-dependent depolarizing ion channels, abnormal cardiac rhythm could be rapidly detected and terminated to restore sinus rhythm in a fully biological and shock-free manner. However, from a translational point of view, it remains unclear how such rhythm restoration can be realized via ion channel gene therapy. Purpose To explore and understand the importance of the distribution and number of BioICD-expressing cardiomyocytes in realizing fully biological restoration of cardiac rhythm. Methods To this purpose, two different realistic gene therapy configurations, i.e. those corresponding to systemic and local transgene delivery, were tested in human ventricular virtual cardiac monolayers. For the systemic delivery group, BioICD-expressing cells were homogeneously distributed (10 random variations) over the tissue with fixed total expression percentage (14 percentages). For the local delivery group, circular areas (7 radii) were given BioICD-expressing cells randomly patterned (10 variations) in a Gaussian distribution with 3 fixed total expression percentages. For both groups, spiral waves were initiated (9 locations) and studied for the following 10 seconds for each test condition, thereby equaling 1260 and 1890 conditions, respectively. Results For systemic delivery, normal rhythm was restored in all cases for >50% BioICD expressing cells, with time till termination being inversely related to the percentage, resulting in only 4.3s and 2.5s for 50% and 100%, respectively. Regarding termination, it was observed that conduction blocks appeared throughout the tissue and subsequently connected to force arrhythmic waves to terminate, while this process remained incomplete in the <50% groups. Local delivery, on the other hand, resulted in islands of ionic heterogeneity, causing attraction and anchoring of the spiral waves in a size and distance-dependent manner. Hence, BioICD-based self-termination was not observed in any of the investigated conditions, leaving spiral waves to persist. Conclusion This study reveals that wide-spread distribution of BioICD-expressing cardiomyocytes is required for the realization of fully biological self-restoration of cardiac rhythm, of which the efficiency is dosage-dependent. Local expression, however, results in stabilization of spiral wave activity. Further exploration of this emerging concept of biological cardioversion may not only expand our understanding of cardiac arrhythmias, but also pave the way to breakthrough advances in arrhythmia management. FUNDunding Acknowledgement Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Research Council (Starting grant 716509) to D.A. Pijnappels.

TRANSITION OF ORDERED WAVES IN NEURONAL NETWORK INDUCED BY DIFFUSIVE POISONING OF ION CHANNELS

2013 ◽  
Vol 21 (01) ◽  
pp. 1350002 ◽  
Author(s):  
LONG HUANG ◽  
JUN MA ◽  
JUN TANG ◽  
FAN LI
Keyword(s):  
Ion Channels ◽  
Spiral Wave ◽  
Spiral Waves ◽  
Channel Noise ◽  
Channel Blocking ◽  
Adjacent Site ◽  
Line Defects ◽  
Ion Channel Blocking ◽  
Wave Induced ◽  
Target Wave

Normal physiological activities are often affected by some drugs, and some ion channels are blocked due to the katogene of drugs. This paper investigates the propagation of ordered waves in neuronal networks induced by diffusive poisoning, where the process is measured by increasing the number of neurons in the poisoned area of the networks. A coefficient of poisoning K is defined to measure the time units from one poisoned site to the adjacent site, a smaller K means that more neurons are poisoned in a certain period (a higher poisoning speed). A statistical factor of synchronization R in the two-dimensional array is defined to detect the transition of spiral waves induced by ion channel blocking. It is confirmed that the evolution of the spiral waves depends on the coefficient of poisoning K and number of poisoned neurons. Furthermore, breakup of the spirals is observed when weak channel noise is considered. Finally, the formation of the spiral wave induced by blocking the target wave with line defects is briefly discussed.

Formation of multi-armed spiral waves in neuronal network induced by adjusting ion channel conductance

2015 ◽  
Vol 29 (07) ◽  
pp. 1550043 ◽  
Author(s):  
Chunni Wang ◽  
Jun Ma ◽  
Bolin Hu ◽  
Wuyin Jin
Keyword(s):  
Ion Channels ◽  
Neuron Model ◽  
Nearest Neighbor ◽  
Spiral Wave ◽  
Spiral Waves ◽  
Channel Conductance ◽  
Transient Period ◽  
Regular Network ◽  
Realistic Neuron ◽  
Armed Spiral

The Hodgkin–Huxley neuron model is used to describe the local dynamics of nodes in a two-dimensional regular network with nearest-neighbor connections. Multi-armed spiral waves emerge when a group of spiral waves rotate the same core synchronously. Here we have numerically investigated how multi-armed spiral waves are formed in such a system. Under the appropriate conditions, multi-armed spiral waves were able to develop as a result of adjusting the conductance of ion channels of particular neurons in the network. In a realistic neuron model, it can be practiced by blocking potassium of ion channels embedded in the membrane of neurons. For example, decreasing the potassium channel conductance in some neurons with a certain transient period can lead to the development of a group of double spirals in a localized area of the network. Furthermore, decreasing the excitability and the external forcing current to zero led to the growth of these double spirals and the formation of a stable multi-armed spiral wave that occupied the network under inhomogeneity.

scholarly journals Gene therapy via canalostomy approach preserves auditory and vestibular functions in a mouse model of Jervell and Lange-Nielsen syndrome type 2

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xuewen Wu ◽  
Li Zhang ◽  
Yihui Li ◽  
Wenjuan Zhang ◽  
Jianjun Wang ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Inner Ear ◽  
Viral Vectors ◽  
Survival Rates ◽  
Semicircular Canals ◽  
Dependent Manner ◽  
Syndrome Type ◽  
Dose Dependent

AbstractMutations in voltage-gated potassium channel KCNE1 cause Jervell and Lange-Nielsen syndrome type 2 (JLNS2), resulting in congenital deafness and vestibular dysfunction. We conducted gene therapy by injecting viral vectors using the canalostomy approach in Kcne1−/− mice to treat both the hearing and vestibular symptoms. Results showed early treatment prevented collapse of the Reissner’s membrane and vestibular wall, retained the normal size of the semicircular canals, and prevented the degeneration of inner ear cells. In a dose-dependent manner, the treatment preserved auditory (16 out of 20 mice) and vestibular (20/20) functions in mice treated with the high-dosage for at least five months. In the low-dosage group, a subgroup of mice (13/20) showed improvements only in the vestibular functions. Results supported that highly efficient transduction is one of the key factors for achieving the efficacy and maintaining the long-term therapeutic effect. Secondary outcomes of treatment included improved birth and litter survival rates. Our results demonstrated that gene therapy via the canalostomy approach, which has been considered to be one of the more feasible delivery methods for human inner ear gene therapy, preserved auditory and vestibular functions in a dose-dependent manner in a mouse model of JLNS2.

DEFECT-LINE DYNAMICS IN OSCILLATORY SPIRAL WAVES

2006 ◽  
Vol 06 (04) ◽  
pp. L379-L386
Author(s):  
STEVEN WU
Keyword(s):  
Critical Point ◽  
Period Doubling ◽  
Spiral Wave ◽  
Chaotic Regime ◽  
Spiral Waves ◽  
Bifurcation Parameter ◽  
Local Dynamics ◽  
Total Length ◽  
Defect Line ◽  
Large Fluctuations

We study defect-line dynamics in a 2-D spiral-wave pair in the Rössler model for its underlying local dynamics in period-N and chaotic regimes with a single bifurcation parameter κ. We find that a spiral wave pair is always stable across the period-doubling cascade and in the chaotic regime. When N ≥ 2 defect lines appear spontaneously and a loop exchange occurs across the defect line. There exists a "critical point" κ c below and above which the time-averaged total length of defect lines L converges to almost constant but different values L1 and L2. When κ > κ c defect lines show large fluctuations due to creation and annihilation processes.

scholarly journals Spiral wave unpinning facilitated by wave emitting sites in cardiac monolayers

2019 ◽  
Vol 475 (2230) ◽  
pp. 20190420
Author(s):  
Shreyas Punacha ◽  
Sebastian Berg ◽  
Anupama Sebastian ◽  
Valentin I. Krinski ◽  
Stefan Luther ◽  
...  
Keyword(s):  
Electric Field ◽  
Electrical Activity ◽  
Spiral Wave ◽  
Electrical Stimulus ◽  
Spiral Waves ◽  
Time Interval ◽  
Field Pulse ◽  
The Core ◽  
Rotating Wave ◽  
Multiple Obstacles

Rotating spiral waves of electrical activity in the heart can anchor to unexcitable tissue (an obstacle) and become stable pinned waves. A pinned rotating wave can be unpinned either by a local electrical stimulus applied close to the spiral core, or by an electric field pulse that excites the core of a pinned wave independently of its localization. The wave will be unpinned only when the pulse is delivered inside a narrow time interval called the unpinning window (UW) of the spiral. In experiments with cardiac monolayers, we found that other obstacles situated near the pinning centre of the spiral can facilitate unpinning. In numerical simulations, we found increasing or decreasing of the UW depending on the location, orientation and distance between the pinning centre and an obstacle. Our study indicates that multiple obstacles could contribute to unpinning in experiments with intact hearts.

scholarly journals Local Cisplatin Delivery in Mouse Reliably Models Sensorineural Ototoxicity Without Systemic Adverse Effects

2021 ◽  
Vol 15 ◽  
Author(s):  
German Nacher-Soler ◽  
Sébastien Lenglet ◽  
Marta Coelho ◽  
Aurélien Thomas ◽  
François Voruz ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Adverse Effects ◽  
Animal Welfare ◽  
Local Delivery ◽  
Significant Loss ◽  
Outer Hair Cells ◽  
Threshold Shift ◽  
Control Group ◽  
Systemic Delivery ◽  
Delivery Model

Cisplatin is a lifesaving chemotherapeutic drug with marked ototoxic adverse effects. Cisplatin-induced hearing loss affects a significant part of cancer-surviving patients and is an unmet clinical need with important socioeconomic consequences. Unfortunately, in current preclinical animal models of cisplatin ototoxicity, which are mainly based on systemic delivery, important morbidity is observed, leading to premature death. This methodology not only raises obvious animal welfare concerns but also increases the number of animals used in ototoxicity studies to compensate for dropouts related to early death. To overcome these important limitations, we developed a local delivery model based on the application of a cisplatin solution directly into the otic bulla through a retroauricular approach. The local delivery model reliably induced significant hearing loss with a mean threshold shift ranging from 10 to 30 dB, strongly affecting the high frequencies (22 and 32 kHz). Importantly, mice did not show visible stress or distress indicators and no significant morbidity in comparison with a traditional systemic delivery control group of mice injected intraperitoneally with 10 mg/kg cisplatin, where significant weight loss >10% in all treated animals (without any recovery) led to premature abortion of experiments on day 3. Mass spectrometry confirmed the absence of relevant systemic uptake after local delivery, with platinum accumulation restricted to the cochlea, whereas important platinum concentrations were detected in the liver and kidney of the systemic cisplatin group. A clear correlation between the cochlear platinum concentration and the auditory threshold shift was observed. Immunohistochemistry revealed statistically significant loss of outer hair cells in the basal and apical turns of the cochlea and an important and statistically significant loss of auditory neurons and synapses in all cochlear regions. In conclusion, local cisplatin delivery induces robust hearing loss with minimal morbidity, thereby offering a reliable rodent model for human cisplatin ototoxicity, reducing the number of animals required and showing improved animal welfare compared with traditional systemic models.

scholarly journals Cardiac Spiral Wave Drifting Due to Spatial Temperature Gradients – a Numerical Study

2018 ◽  
Author(s):  
Guy Malki ◽  
Sharon Zlochiver
Keyword(s):  
Numerical Simulations ◽  
Single Cell ◽  
Numerical Study ◽  
Spiral Wave ◽  
Spiral Waves ◽  
Temperature Gradients ◽  
Effect Of Temperature ◽  
Local Perturbation ◽  
Marginal Effect ◽  
Spatial Temperature

ABSTRACTCardiac rotors are believed to be a major driver source of persistent atrial fibrillation (AF), and their spatiotemporal characterization is essential for successful ablation procedures. However, electrograms guided ablation have not been proven to have benefit over empirical ablation thus far, and there is a strong need of improving the localization of cardiac arrhythmogenic targets for ablation. A new approach for characterize rotors is proposed that is based on induced spatial temperature gradients (STGs), and investigated by theoretical study using numerical simulations. We hypothesize that such gradients will cause rotor drifting due to induced spatial heterogeneity in excitability, so that rotors could be driven towards the ablating probe. Numerical simulations were conducted in single cell and 2D atrial models using AF remodeled kinetics. STGs were applied either linearly on the entire tissue or as a small local perturbation, and the major ion channel rate constants were adjusted following Arrhenius equation. In the AF-remodeled single cell, recovery time increased exponentially with decreasing temperatures, despite the marginal effect of temperature on the action potential duration. In 2D models, spiral waves drifted with drifting velocity components affected by both temperature gradient direction and the spiral wave rotation direction. Overall, spiral waves drifted towards the colder tissue region associated with global minimum of excitability. A local perturbation with a temperature of T=28°C was found optimal for spiral wave attraction for the studied conditions. This work provides a preliminary proof-of-concept for a potential prospective technique for rotor attraction. We envision that the insights from this study will be utilize in the future in the design of a new methodology for AF characterization and termination during ablation procedures.

"SPIRAL WAVE–TRAVELING CLUSTERING" INTERMITTENCY AND 1/f-NOISE IN A 2D COUPLED MAP LATTICE

1999 ◽  
Vol 09 (05) ◽  
pp. 929-937 ◽  
Author(s):  
MARK A. PUSTOVOIT ◽  
VALERY I. SBITNEV
Keyword(s):  
Probability Density ◽  
Exponential Decay ◽  
Power Law ◽  
Strange Attractor ◽  
Spiral Wave ◽  
Spiral Waves ◽  
Coupled Map Lattice ◽  
The Self ◽  
Saddle Node Bifurcation ◽  
Self Organized

Intermittency of checkerboard spiral waves and traveling clusterings originating from sudden shrinking of the strange attractor of the 2D CML in the neighborhood of the saddle-node bifurcation boundary is found. A power-law probability density for lifetimes in the spiral wave (laminar) phase is observed, while in the checkerboard clusterings (bursting) phase the above quantity exhibits an exponential decay. This difference can be interpreted through the self-organized behavior of the spiral waves, and the passive relaxation of the disordered checkerboard clusterings.

scholarly journals Predictability of spatio-temporal patterns in a lattice of coupled FitzHugh–Nagumo oscillators

2013 ◽  
Vol 10 (81) ◽  
pp. 20121016 ◽  
Author(s):  
Miriam Grace ◽  
Marc-Thorsten Hütt
Keyword(s):  
Dynamical System ◽  
Spiral Wave ◽  
Temporal Patterns ◽  
Spiral Waves ◽  
Generic Model ◽  
Homogeneous State ◽  
Drift Speed ◽  
Statistical Fluctuations ◽  
Self Organized ◽  
Spatio Temporal

In many biological systems, variability of the components can be expected to outrank statistical fluctuations in the shaping of self-organized patterns. In pioneering work in the late 1990s, it was hypothesized that a drift of cellular parameters (along a ‘developmental path’), together with differences in cell properties (‘desynchronization’ of cells on the developmental path) can establish self-organized spatio-temporal patterns (in their example, spiral waves of cAMP in a colony of Dictyostelium discoideum cells) starting from a homogeneous state. Here, we embed a generic model of an excitable medium, a lattice of diffusively coupled FitzHugh–Nagumo oscillators, into a developmental-path framework. In this minimal model of spiral wave generation, we can now study the predictability of spatio-temporal patterns from cell properties as a function of desynchronization (or ‘spread’) of cells along the developmental path and the drift speed of cell properties on the path. As a function of drift speed and desynchronization, we observe systematically different routes towards fully established patterns, as well as strikingly different correlations between cell properties and pattern features. We show that the predictability of spatio-temporal patterns from cell properties contains important information on the pattern formation process as well as on the underlying dynamical system.

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