Modeling cardiac complexity: Advancements in myocardial models and analytical techniques for physiological investigation and therapeutic development in vitro

FIG. 1.. (a) An adult murine cardiomyocyte (CM), stained for sarcomeric α-actinin. Sarcomeres are continuous across the bundle of myofibrils that form the cell.21 Reprinted with permission from Ackers-Johnson et al., Circ. Res. 119(8), 909–920 (2016). Copyright 2016 Wolters Kluwer Health, Inc. (b) The cardiac action potential (top) is composed of four distinct phases, each with a specific ionic flux component (bottom). The cardiomyocyte produces a field potential (middle) that is highly correlated with the shape of its action potential.22 Reprinted with permission from Tertoolen et al., Biochem. Biophys. Res. Commun. 497(4), 1135–1141. Copyright 2018 Author(s), licensed under a Creative Commons Attribution 4.0 International License. (c) The resting membrane potential, and the precise shape of the action potential is specific to the CM subtype; nodal, atrial, and ventricular CMs have unique electrophysiological fingerprints.8 Reprinted with permission from Liu et al., Adv. Drug Delivery Rev. 96, 253–273. Copyright 2016 Elsevier. (d) The flux of contraction-enabling Ca2+ into the cytosol (black) is correlated with cell contraction strain (blue).23 Reprinted with permission from Ahola et…

FIG. 2.. The role of advancing techniques to assess the cardiomyocyte function in vitro in the workflow to improved pharmaceutical testing and clinical outcomes. Both hypothesis- and discovery-driven research studies push each other forward, while informing iterations of cell and tissue models and devices, modalities, and techniques used in experimentation. The discoveries from fundamental science can then be translated to the clinic, while clinical findings can be used as a starting point for further fundamental inquiry.

FIG. 3.. Negative correlation between the current usability of representative CM models and their final utility in advancing the field as a function of their ability to recapitulate complex and emergent CM physiological phenomena such as electrophysiology, contractility, signaling, and metabolism. By using improved functional characterization, which fuels improved experimentation, both the ease of use and scientific value and translatability can be increased.

FIG. 4.. (a) Common principles underlying most measurements of contraction; an axial force can be measured directly using an isometric or strain gauge force transducer. Conversely, during an isotonic contraction, perpendicular cell thickening can be used as a correlative measurement due to the conservation of volume within a contracting cell. The titin structure within the CM offers a baseline of passive resistance (T⇀passive), to which the applied force vector from active contraction (F⇀a) is added. (b) Principles of contraction within a sarcomere of stable A-band dimensions that allow for sarcomeric shortening measurements of isotonic (above) and isometric contraction (below) such as seen in TEM studies.263 The scale bar on the left is 1 μm. (c) The heart makes use of both near-isotonic (auxotonic) and isometric contractions with each cycle, as illustrated by a standard pressure-volume loop. The cycle occurs in a counter-clockwise direction, with systole and diastole ending before isometric phases at the top-left and bottom-right corners of the loop, respectively. Passive diastolic filling at near-constant pressure results in eccentric contraction in the myocardium, which corresponds to…