Dataset Information

Mechano-Electric Coupling and Arrhythmogenic Current Generation in a Computational Model of Coupled Myocytes.

ABSTRACT: A wide range of arrhythmogenic phenotypes have been associated with heterogeneous mechanical dyskinesis. Pro-arrhythmic effects are often associated with dysregulated intra-cellular calcium handling, especially via the development of intra- and inter-cellular calcium waves. Experimental evidence suggests that mechanical strain can contribute to the generation and maintenance of these calcium waves via a variety of mechano-electric coupling mechanisms. Most model studies of mechano-electric coupling mechanisms have been focused on mechano-sensitive ion channels, even though experimental studies have shown that intra- and inter-cellular calcium waves triggered by mechanical perturbations are likely to be more prevalent pro-arrhythmic mechanisms in the diseased heart. A one-dimensional strongly coupled computational model of electromechanics in rabbit ventricular cardiomyocytes showed that specific myocyte stretch sequences can modulate the susceptibility threshold for delayed after-depolarizations. In simulations of mechanically-triggered calcium waves in cardiomyocytes coupled to fibroblasts, susceptibility to calcium wave propagation was reduced as the current through the gap junction caused current drain from the myocytes. In 1D multi-cellular arrays coupled via gap junctions, mechanically-induced waves may contribute to synchronizing arrhythmogenic calcium waves and after-depolarizations.

SUBMITTER: Timmermann V

PROVIDER: S-EPMC7758443 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Mechano-Electric Coupling and Arrhythmogenic Current Generation in a Computational Model of Coupled Myocytes.

Timmermann Viviane V McCulloch Andrew D AD

Frontiers in physiology 20201210

A wide range of arrhythmogenic phenotypes have been associated with heterogeneous mechanical dyskinesis. Pro-arrhythmic effects are often associated with dysregulated intra-cellular calcium handling, especially <i>via</i> the development of intra- and inter-cellular calcium waves. Experimental evidence suggests that mechanical strain can contribute to the generation and maintenance of these calcium waves <i>via</i> a variety of mechano-electric coupling mechanisms. Most model studies of mechano- ...[more]

PMID: 33362569

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Project description:BACKGROUND:The activation of stretch-activated channels (SACs) in cardiac myocytes, which changes the phases of action potential repolarization, is proven to be highly efficient for the conversion of atrial fibrillation. The expression of Na+ current in myofibroblasts (Mfbs) regenerates myocytes' action potentials, suggesting that Mfbs play an active role in triggering cardiac rhythm disturbances. Moreover, the excitation of mechano-gated channels (MGCs) in Mfbs depolarizes their membrane potential and contributes to the increased risk of post-infarct arrhythmia. Although these electrophysiological mechanisms have been largely known, the roles of these currents in cardiac mechanics are still debated. In this study, we aimed to investigate the mechanical influence of these currents via mathematical modeling. A novel mathematical model was developed by integrating models of human atrial myocyte (including the stretch-activated current, Ca2+-force relation, and mechanical behavior of a single segment) and Mfb (including our formulation of Na+ current and mechano-gated channels' current). The effects of the changes in basic cycle length, number of coupled Mfbs and intercellular coupling conductance on myocyte mechanical properties were compared. RESULTS:Our results indicated that these three currents significantly regulated myocyte mechanical parameters. In isosarcometric contraction, these currents increased segment force by 13.8-36.6% and dropped element length by 12.1-31.5%. In isotonic contraction, there are 2.7-5.9% growth and 0.9-24% reduction. Effects of these currents on the extremum of myocyte mechanical parameters become more significant with the increase of basic cycle length, number of coupled Mfbs and intercellular coupling conductance. CONCLUSIONS:The results demonstrated that stretch-activated current in myocytes and Na+ current and mechano-gated channels' current in Mfbs significantly influenced myocyte mechanical behavior and should be considered in future cardiac mechanical mathematical modeling.

Project description:RationaleIntercellular uncoupling and Ca2+ (Ca) mishandling can initiate triggered ventricular arrhythmias. Spontaneous Ca release activates inward current which depolarizes membrane potential (Vm) and can trigger action potentials in isolated myocytes. However, cell-cell coupling in intact hearts limits local depolarization and may protect hearts from this arrhythmogenic mechanism. Traditional optical mapping lacks the spatial resolution to assess coupling of individual myocytes.ObjectiveWe investigate local intercellular coupling in Ca-induced depolarization in intact hearts, using confocal microscopy to measure local Vm and intracellular [Ca] simultaneously.Methods and resultsWe used isolated Langendorff-perfused hearts from control (CTL) and heart failure (HF) mice (HF induced by transaortic constriction). In CTL hearts, 1.4% of myocytes were poorly synchronized with neighboring cells and exhibited asynchronous (AS) Ca transients. These AS myocytes were much more frequent in HF (10.8% of myocytes, P<0.05 versus CTL). Local Ca waves depolarized Vm in HF but not CTL hearts, suggesting weaker gap junction coupling in HF-AS versus CTL-AS myocytes. Cell-cell coupling was assessed by calcein fluorescence recovery after photobleach during intracellular [Ca] recording. All regions in CTL hearts exhibited faster calcein diffusion than in HF, with HF-AS myocyte being slowest. In HF-AS, enhancing gap junction conductance (with rotigaptide) increased coupling and suppressed Vm depolarization during Ca waves. Conversely, in CTL hearts, gap junction inhibition (carbenoxolone) decreased coupling and allowed Ca wave-induced depolarizations. Synchronization of Ca wave initiation and triggered action potentials were observed in HF hearts and computational models.ConclusionsWell-coupled CTL myocytes are effectively voltage-clamped during Ca waves, protecting the heart from triggered arrhythmias. Spontaneous Ca waves are much more common in HF myocytes and these AS myocytes are also poorly coupled, enabling local Ca-induced inward current of sufficient source strength to overcome a weakened current sink to depolarize Vm and trigger action potentials.

Dataset Information

Mechano-Electric Coupling and Arrhythmogenic Current Generation in a Computational Model of Coupled Myocytes.

Publications

Mechano-Electric Coupling and Arrhythmogenic Current Generation in a Computational Model of Coupled Myocytes.

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