About this Research Topic
The heart is a mechanically active organ constantly subjected to internal and external mechanical cues. Mechanical effects on the heart muscle can significantly modulate the regulation of its contractility, manifesting themselves in the form of various mechano-regulatory feedback loops, e.g. mechano-calcium, mechano-electric, and mechano-metabolic ones. On the one hand, these regulations help the healthy myocardium to adapt to its mechanical environment, including conditions of the mechanical interactions between heterogeneous cardiomyocytes in the heart chamber walls. On the other hand, the pathological manifestations of these feedback loops can be quite dramatic: i.e., they can cause heart rhythm disturbances and even lead to sudden cardiac arrest.
For example, it has been shown that mechano-dependence of the microtubule, t-tubule, and sarcoplasmic reticulum topology may contribute via the calcium induced calcium release to the mechano-calcium feedback. Another very important circuit of the mechano-calcium feedback loops is associated with the load- and/or length-dependent kinetics of the Ca2+-TnC complexes regulating calcium activation of the cardiomyocyte contractions. There are many arguments in favor of the point of view that various mechano-calcium regulatory loops contribute significantly to a number of phenomena pertaining to fast and slow force responses of the heart muscle to stretches and other types of deformation.
Moreover, mechano-calcium coupling can be a trigger for mechano-electric feedbacks, since by influencing the shape and duration of the calcium transient during mechanical twitch they can modulate - via the sodium-calcium exchange - the shape and duration of the action potential.
A more direct way of the mechano-electric feedbacks appears owing to the mechano-sensitive ion channels in the cardiomyocyte membrane. While the important role of these channels is generally recognized, many details remain poorly understood, including the pattern of the response of the conductivity of such channels to the stretch, as well their localization in the cell membrane and their ionic specificity.
In recent years, several studies appeared that demonstrated influence of mechanics on the energetic metabolism, in particular on the feedback between the cardiomyocyte contractions and mitochondrial functions via its deformations. It can be expected that load-dependency in mitochondrial functions, including Ca2+ buffering, ATP production and ROS generation, in turn, affects mechano-calcium and therefore mechano-electric feedback, and resultant load-dependency in mechanoenergetics of the heart.
A great deal of attention to all mentioned above regulatory loops is being given in many research laboratories. Elucidation of the mechanisms of contribution of mechano-calcium, mechano-electric, and mechano-metabolic feedbacks and of their possible interplays to the myocardium contractility requires the involvement of both experimental studies and theoretical works using mathematical modeling.
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