Calcium Handling Defects and Cardiac Arrhythmia Syndromes

Figure 1. Schematic diagram of the cardiac excitation-contraction coupling. (A) Structures involved in Ca2+ transport in cardiac mycocytes. Red trace shows a typical systolic Ca2+ transient. Briefly, during the Ca2+-induced Ca2+ release process, Ca2+ entering the cell via L-type Ca2+ channels releases a larger amount of Ca2+ from the sarcoplasmic reticulum to activate the contractile machinery. Ca2+ extrusion requires NCX, PMCA, and SERCA. (B) Detailed section of the dyad showing the major proteins involved in Ca2+ cycling. Reproduced from Eisner et al. used with permission (Eisner et al., 2017). β-AR, β adrenoceptor; NCX, Na+-Ca2+ exchange; PMCA, plasma membrane Ca2+-ATPase; RyR, ryanodine receptor; SERCA, sarco/endoplasmic reticulum Ca2+-ATPase; CSQ, calsequestrin; PLN, phospholamban.

Figure 2. Cellular physiological electrical activities. (A) Transmural heterogeneity in the cardiac ventricular action potential, showing (from left to right) recordings from: subendocardium, midmyocardium, and subepicardium. Note the spike-and-dome action potential configuration in the subepicardium. ENDO, subendocardial mycocyte; MID, midmyocardial “M” myocyte; EPI, subepicardial myocyte. (B) Series of typical subepicardial ventricular action potentials at normal pacing activity.

Figure 3. Cellular pathophysiological electrical activities. (A) Phase 2 early afterdepolarization (EAD), (B) Phase 3 EAD, (C) Late-phase 3 EAD, (D) Delayed afterdepolarization (DAD) manifesting triggered activity. Ca2+ has an important role in generating afterdepolarizations. Underlying mechanisms are described in the relevant sections. (E) Automaticity (spontaneous membrane potential oscillations) occurs if the membrane potential of the cells shift to more positive values causing abnormal activity. (F) Cardiac voltage alternans, manifesting a long-short-long-short pattern. (G) Short term beat-to-beat variability of the action potential duration. (a), (b), and (c) show different time points after interventions that increase action potential duration and beat-to-beat variability leading to EAD generation. Right panel of (G) shows action potential duration at 90% of the repolarization (APD90) as a function of time.

Figure 4. The origin of the heartbeat: coupled-clock pacemaker system in the sinoatrial cells. The pacemaker activity of the SA node originates from the membrane and calcium clock mechanisms. The former is composed of the sarcolemmal channel proteins, and the latter results from sarcoplasmic reticulum and sarcoplasmic Ca2+ turnover. At end of the SA action potential the hyperpolarization-activated If depolarizes the membrane to a level where Ca2+ channels open. In addition, during late diastole, spontaneous SR Ca2+ releases further depolarize the membrane by activating INCX. Ca2+ can bind to calmodulin and activate adenylyl cyclase (AC). High constitutive activation of AC leading to high basal level of cAMP (which is needed for protein kinase A-dependent phosphorylation) in SA node cells has been suggested to contribute to the Ca2+ overload state. PKA-dependent phosphorylation of phospholamban, ICa,L, and RyR promotes spontaneous Ca2+ release. Blue shows the membrane clock and red shows the calcium clock mechanism. Solid arrows show the Ca2+-induced Ca2+ release process and spontaneous Ca2+ release events via RyR; dashed arrows show the phosphorylation targets of the cAMP–PKA pathway.…

Figure 5. Basic mechanisms of ectopic activity. (A) Factors involved in the generation of early afterdepolarizations (EAD). In general, EADs occur when outward currents are reduced (reduced repolarization reserve) and/or the inward currents are enhanced. The currently known types of EADs are consequencies of different etiologies, indicated on (A). Detailed description in the text. Membrane potential recording shows a typical phase 2 EAD. (B) Delayed afterdepolarizations (DAD) originate from Ca2+ overload and consequently, spontaneous SR Ca2+ release which, in turn, generates a depolarizing transient inward (Iti) current. Suprathreshold depolarization can elicit triggered activity. Membrane potential recording shows a typical DAD. EAD, early afterdepolarization; DAD, delayed afterdepolarization; ICa,L, L-type Ca2+ current; INa, Na+ current; IKs, slow component of delayed rectifier K+ current; IKr, rapid component of delayed rectifier K+ current; IK1, inward rectifier K+ current; INCX, Na+-Ca2+ exchange; INS, nonselective Ca2+-sensitive cationic currents; ICl(Ca), Ca2+-activated chloride current; Iti, transient outward current; RyR, ryanodine receptor; SR, sarcoplasmic reticulum; SERCA,…

Figure 6. Role of gap junctions in propagating of the cardiac action potential. (A) The cardiac tissue is eletrically homogenous if the adjacent cells are coupled by gap junction channels. The anisotropic nature of gap junction channel distribution favors longitudinal over transversal conduction. (B) Conditions that decrease or abolish coupling between the cells may cause a unidirectional conduction block and as the electrical impulse propagates around the block it can re-excite those tissue regions due to differences in refractoriness. Insert shows cell-cell connections via gap junction channels. The main causes of uncoupling of the cells (showed in red) are elevated intracellular Ca2+ concentration, reduction in H+ concentration, or lower levels of ATP. Cx, connexon; ATP, adenosine triphosphate.

Figure 7. Abnormal impulse conduction. Circus movement reentry types. (A) Reentrant wave travels around an anatomical obstacle. If the cardiac tissue around the obstacle is homogenous the impulse conduction is favored in both directions. However, if the tissue is heterogenous (i.e. dispersion of refractoriness), unidirectional block can form initating a reentry circuit. Excitable gap consists of tissue regions that fully and/or partially recovered from refractory period, therefore excitable. (B) Circuit movement reentry can form in the absence of an anatomical obstacle (functional block). In the leading circle model the length of the circuit is not determined by the pathway around an obstacle, but rather by conduction velocity, refractory period, and stimulating efficacy where (in the absence of an obstacle) a shortcut of the circuit is possible. Spiral waves reentry (or scroll wave if three-dimensional) drifts through the tissue without an obstacle and the main wave can break up and radiate waves to the neighboring regions. In the model of figure-of-8 the circulating waves appear in pairs and the wavefront can circulate around the functional blocks clockwise and counterclockwise. If the…