Ultrastructure and cardiac impulse propagation: scaling up from microscopic to macroscopic conduction

Figure 1. Subcellular and cellular ultrastructure A, light micrograph of cardiac muscle fibres from a canine myocardium (upper) and a drawing of the myocytes showing myocyte connections at intercalated discs (IDs, examples labelled by arrows). Adapted from Hoyt et al. (1989). B, transmission electron microscopy image of the adult murine heart showing gap junctions (labelled as ‘GJ’), desmosomes (labelled as ‘D’) and mitochondria (labelled as ‘M’). Adapted from Delmar and Liang (2012). C, Cx43 clusters in intercalated discs in an isolated ventricular myocyte. Adapted from Severs et al. (2004). D, colocalization of Cx43 (green) and Nav1.5 (red) in IDs. Adapted from Raisch et al. (2018).

Figure 2. T‐tubular structures and intracellular action potential conduction A, a 3D view of T‐tubular network in a rat ventricular myocyte, adapted from Soeller and Cannell (1999). B, T‐tubule remodelling in heart failure, adapted from Song et al. (2006). C, action potential conduction in a failing myocyte. Left: representative transmembrane image of a heart failure myocyte. Right: normalized fluorescence traces from the scanned line indicated in the left panel: SS and TT1 show regular action potentials, TT2 and TT3 display non‐regenerative electrical responses, and TT4 highlights local arrhythmic events (blue asterisks). Adapted from Sacconi et al. (2012).

Figure 3. Tissue‐ and organ‐scale ultrastructure A, Upper: reconstructed volume of rat left ventricular free‐wall myocardium. Lower: transmural slice from the reconstructed volume showing a complex network of cleavage planes that course between layers of myocytes. Each layer is of an order of 80 µm in thickness. Adapted from Hooks et al. (2002). B, His‐Purkinje network (dark brown) in a rabbit heart. Adapted from Atkinson et al. (2011). C, high‐magnitude image of nerve fibre distribution in the heart. Colour is the diameter of the nerve as indicated by the colour bar. Adapted from Zhu et al. (2022). D, constructed electron micrograph showing a vesiculated nerve (dark colour) process within a sarcolemma‐lined tunnel inside a nodal cell. Adapted from Thaemert (1970).

Figure 4. Discontinuous conduction A, a 2D tissue model consisting of 33 myocytes of different cell sizes and geometries as well as the distribution of gap junctions. The inset below shows computational grids (resolution: 10 × 10 × 11.3 µm3) of five cells from the 33‐cell tissue. For details of the model see Spach & Heidlage (1995) and Spach et al. (2000). B, isochrones within each of the five myocytes during propagation (blue arrow) along the longitudinal axis of the cells. The isochrones are separated by 4 µs. Propagation directions inside the cells are all from right to left. C, same as B but during propagation (blue arrow) along the transverse axis of the cells. The isochrones are separated by 3 µs. Propagation directions inside the cells are indicated by arrows.

Figure 5. Perinexus and ephaptic coupling A, scanning electron microscopy image of IDs in monkey ventricular myocytes. Adapted from Zhang et al. (1996). B, tomographic electron microscopy section and 3D rendered representation of a portion of the intercalated disc of mouse ventricular tissue. Top: virtual section of tomogram showing different typical ID structures: AC, area composita; D, desmosome; GJ, gap junction; Mf, myofibrils; and Mt, mitochondria. Bottom: a 3D rendered model of the ID. Adapted from Leo‐Macias, Agullo‐Pascual, Delmar (2016). C, schematic diagram illustrating the structural organization of channels within the perinexus. The transmission electron micrograph with the gap junction is highlighted in green, the perinexus in orange and the desmosome in blue. Adapted from Rhett et al. (2013). D, schematic diagram illustrating ephaptic coupling. Depolarization of Cell 1 causes Na+ ions to enter Cell 1 from the cleft or perinexus (orange), which lowers the potential in the cleft (ϕc). The lowering of ϕc results in an increase in transmembrane potential (Vm2=ϕi2−ϕc) of Cell 2. Once Vm2 is higher than the Na+ channel activation threshold, the Na+ channels activate, depolarizing…

Figure 6. Schematic diagrams illustrating conduction in cardiac tissue A, action potential conduction in normal tissue. B, action potential conduction in diseased tissue. Dashed arrows indicated weakened or failed conduction.

Figure 7. Schematic diagram illustrating multi‐scale regulation of cardiac conduction and excitation–contraction coupling At the molecular and subcellular scale, a genetic mutation or a drug may alter the protein/signalling network and the localization of the proteins. At the cellular scale, the molecular and subcellular changes alter the action potential dynamics and Ca2+ cycling. At the tissue and organ scale, the coupling of cells gives rise to tissue‐scale phenomena (such as conduction and re‐entry), which are affected by the ultrastructural details occurring at the molecular, subcellular and cellular scales. At the systems scales, interactions between different organs (such as the brain and kidney) via the nervous system or chemicals give rise to the systems‐level phenomena (such as ECG or symptoms of diseases). At the population scale, a genetic mutation or a drug may exhibit an effect on one individual but not another.