Arrhythmogenic Right Ventricular Cardiomyopathy: Considerations from in Silico Experiments

Wilders, Ronald

doi:10.3389/fphys.2012.00168

Cited by 14 publications

(8 citation statements)

References 76 publications

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“…While these EHTs recapitulated the loss of desmoplakin and connexin-43, we did not see the expected change in electrical propagation. Numerical simulations have shown that a 50% loss in gap junction conductance leads to only modest changes in conduction velocity (26), hence the observed decrease in connexin-43 may not be sufficient to induce impaired conduction. This is in line with another study, which reported arrhythmogenic potential in an ACM model system in spite of normal conduction velocity (27).…”

Section: Discussionmentioning

confidence: 99%

Patient mutations linked to arrhythmogenic cardiomyopathy enhance calpain-mediated desmoplakin degradation

Ng¹,

Manring²,

Papoutsidakis³

et al. 2019

JCI Insight

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Section: Discussionmentioning

confidence: 99%

Patient mutations linked to arrhythmogenic cardiomyopathy enhance calpain-mediated desmoplakin degradation

Ng¹,

Manring²,

Papoutsidakis³

et al. 2019

JCI Insight

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“…As in other studies (Shaw and Rudy, 1997 ; Thomas et al, 2003 ; Wilders, 2012 ), the entire cell length (of 74 μm) was used as the spatial discretization element, with elements connected by the lumped myoplasmic resistance (calculated from the myocyte dimensions and the myoplasmic resistivity of 150 Ω·cm) and gap junctional resistance. At the selected gap junctional conductance of 6 nS, this lumped resistance was almost completely determined by the gap junctional resistance (Wilders, 2012 ). The aforementioned Euler-type integration scheme was used for numerical integration.…”

Section: Methodsmentioning

confidence: 99%

KV4.3 Expression Modulates NaV1.5 Sodium Current

et al. 2018

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In cardiomyocytes, the voltage-gated transient outward potassium current (Ito) is responsible for the phase-1 repolarization of the action potential (AP). Gain-of-function mutations in KCND3, the gene encoding the Ito carrying KV4.3 channel, have been associated with Brugada syndrome (BrS). While the role of Ito in the pro-arrhythmic mechanism of BrS has been debated, recent studies have suggested that an increased Ito may directly affect cardiac conduction. However, the effects of an increased Ito on AP upstroke velocity or sodium current at the cellular level remain unknown. We here investigated the consequences of KV4.3 overexpression on NaV1.5 current and consequent sodium channel availability. We found that overexpression of KV4.3 protein in HEK293 cells stably expressing NaV1.5 (HEK293-NaV1.5 cells) significantly reduced NaV1.5 current density without affecting its kinetic properties. In addition, KV4.3 overexpression decreased AP upstroke velocity in HEK293-NaV1.5 cells, as measured with the alternating voltage/current clamp technique. These effects of KV4.3 could not be explained by alterations in total NaV1.5 protein expression. Using computer simulations employing a multicellular in silico model, we furthermore demonstrate that the experimentally observed increase in KV4.3 current and concurrent decrease in NaV1.5 current may result in a loss of conduction, underlining the potential functional relevance of our findings. This study gives the first proof of concept that KV4.3 directly impacts on NaV1.5 current. Future studies employing appropriate disease models should explore the potential electrophysiological implications in (patho)physiological conditions, including BrS associated with KCND3 gain-of-function mutations.

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“…Whereas longitudinal and transverse conduction velocities (CV L and CV T , respectively) are on the order of CV L ~ 20 cm/s and CV T ~ 10 cm/s for engineered tissues, they are CV L ~70 cm/s and CV T ~25 cm/s for whole human left ventricles (Table 3). Conduction velocity depends on gap junctional conductance (in silico: [100]) that is partly determined by the activity of gap junction channel proteins, the assembly and function of which may be limited in vitro using previously dissociated cells [101]. Similarly, contractile stresses generated by whole organs are larger than those generated by engineered tissues.…”

Section: Design Criteria For Engineered Cardiac Tissuesmentioning

confidence: 99%

Fibrous scaffolds for building hearts and heart parts

Capulli

MacQueen

Sheehy

et al. 2016

Advanced Drug Delivery Reviews

111

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Extracellular matrix (ECM) structure and biochemistry provide cell-instructive cues that promote and regulate tissue growth, function, and repair. From a structural perspective, the ECM is a scaffold that guides the self-assembly of cells into distinct functional tissues. The ECM promotes the interaction between individual cells and between different cell types, and increases the strength and resilience of the tissue in mechanically dynamic environments. From a biochemical perspective, factors regulating cell-ECM adhesion have been described and diverse aspects of cell-ECM interactions in health and disease continue to be clarified. Natural ECMs therefore provide excellent design rules for tissue engineering scaffolds. The design of regenerative three-dimensional (3D) engineered scaffolds is informed by the target ECM structure, chemistry, and mechanics, to encourage cell infiltration and tissue genesis. This can be achieved using nanofibrous scaffolds composed of polymers that simultaneously recapitulate 3D ECM architecture, high-fidelity nanoscale topography, and bio-activity. Their high porosity, structural anisotropy, and bio-activity present unique advantages for engineering 3D anisotropic tissues. Here, we use the heart as a case study and examine the potential of ECM-inspired nanofibrous scaffolds for cardiac tissue engineering. We asked: Do we know enough to build a heart? To answer this question, we tabulated structural and functional properties of myocardial and valvular tissues for use as design criteria, reviewed nanofiber manufacturing platforms and assessed their capabilities to produce scaffolds that meet our design criteria. Our knowledge of the anatomy and physiology of the heart, as well as our ability to create synthetic ECM scaffolds have advanced to the point that valve replacement with nanofibrous scaffolds may be achieved in the short term, while myocardial repair requires further study in vitro and in vivo.

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Arrhythmogenic Right Ventricular Cardiomyopathy: Considerations from in Silico Experiments

Cited by 14 publications

References 76 publications

Patient mutations linked to arrhythmogenic cardiomyopathy enhance calpain-mediated desmoplakin degradation

Patient mutations linked to arrhythmogenic cardiomyopathy enhance calpain-mediated desmoplakin degradation

KV4.3 Expression Modulates NaV1.5 Sodium Current

Fibrous scaffolds for building hearts and heart parts

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