Multidimensional Role of Calcium in Atrial Fibrillation
Multidimensional Role of Calcium in Atrial Fibrillation
Figure 1 illustrates the basic electrophysiological mechanisms leading to AF, highlighting the role of Ca-related processes. A brief overview will be presented here; for details see relevant review articles. Atrial fibrillation can be maintained by rapid focal ectopic activity (e.g. from the pulmonary veins) or by re-entry (Figure 1A). Re-entry requires a vulnerable substrate, as well as a trigger usually provided by spontaneous focal ectopic discharge. The most common causes of focal ectopic activity are afterdepolarizations (Figure 1B): delayed afterdepolarizations (DADs) occurring after full repolarization or early afterdepolarizations (EADs) preceding full repolarization [typically towards the end of the action potential (AP) plateau or early in phase 3 repolarization]. Delayed afterdepolarizations are caused by inward Na,Ca exchange (NCX) current (INCX), generated by a transient diastolic rise in cytoplasmic Ca concentration: the additional Ca is exchanged for extracellular Na in a 1:3 ionic ratio, generating a net inward movement of positive ions. When DADs reach excitation threshold, spontaneous APs arise. Early afterdepolarizations occur when the AP is excessively prolonged [e.g. by increased inward L-type Ca current (ICaL) or late Na current (INaL), or by reduced K currents], allowing I CaL to recover from inactivation and depolarize the cell by allowing Ca to enter. Early afterdepolarizations cause ectopic firing by depolarizing surrounding tissue to excitation threshold. I NCX flows during the AP plateau and contributes to EAD-generating AP prolongation.
(Enlarge Image)
Figure 1.
Basic mechanisms underlying atrial fibrillation. (A) Atrial fibrillation can be maintained by rapid focal ectopic activity or re-entry. Re-entry requires a vulnerable substrate and initiating trigger. (B) Cellular mechanisms of focal activity. Ca-related functions are in red. (C) Determinants of atrial fibrillation maintaining re-entrant activity. Left: wavelength = refractory period × conduction velocity, determines size of functional re-entry circuits. Right: reduced wavelength allows more simultaneous circuits, making atrial fibrillation termination less likely. Wavelength can be reduced by decreased action potential duration. Ca-related functions that reduce wavelength include decreased I CaL and increased Ca-dependent K current (I KCa).
Re-entry maintenance depends on critical refractoriness and conduction conditions (Figure 1C). The 'leading circle' concept posits that functional re-entry establishes itself in the minimum sized circuit for re-entry maintenance, given by the distance ('wavelength') the impulse travels in one refractory period (RP): wavelength = RP × conduction velocity. When the number of circuits that the atria can contain is small (Figure 1C, left), re-entry is unstable and AF self-terminates. When the wavelength is reduced (e.g. when RP decreases), the circuits are smaller and more numerous, simultaneous termination of all circuits is unlikely, and AF is sustained (Figure 1C, right). Refractory period depends on action potential duration (APD). Action potential duration is reduced by decreasing inward current (ICaL), or by increasing outward K current. Recent genomic work suggests that a Ca-dependent K current plays an important role in AF, likely by controlling APD.
Basic Mechanistic Determinants of Atrial Fibrillation and Role of Ca
Figure 1 illustrates the basic electrophysiological mechanisms leading to AF, highlighting the role of Ca-related processes. A brief overview will be presented here; for details see relevant review articles. Atrial fibrillation can be maintained by rapid focal ectopic activity (e.g. from the pulmonary veins) or by re-entry (Figure 1A). Re-entry requires a vulnerable substrate, as well as a trigger usually provided by spontaneous focal ectopic discharge. The most common causes of focal ectopic activity are afterdepolarizations (Figure 1B): delayed afterdepolarizations (DADs) occurring after full repolarization or early afterdepolarizations (EADs) preceding full repolarization [typically towards the end of the action potential (AP) plateau or early in phase 3 repolarization]. Delayed afterdepolarizations are caused by inward Na,Ca exchange (NCX) current (INCX), generated by a transient diastolic rise in cytoplasmic Ca concentration: the additional Ca is exchanged for extracellular Na in a 1:3 ionic ratio, generating a net inward movement of positive ions. When DADs reach excitation threshold, spontaneous APs arise. Early afterdepolarizations occur when the AP is excessively prolonged [e.g. by increased inward L-type Ca current (ICaL) or late Na current (INaL), or by reduced K currents], allowing I CaL to recover from inactivation and depolarize the cell by allowing Ca to enter. Early afterdepolarizations cause ectopic firing by depolarizing surrounding tissue to excitation threshold. I NCX flows during the AP plateau and contributes to EAD-generating AP prolongation.
(Enlarge Image)
Figure 1.
Basic mechanisms underlying atrial fibrillation. (A) Atrial fibrillation can be maintained by rapid focal ectopic activity or re-entry. Re-entry requires a vulnerable substrate and initiating trigger. (B) Cellular mechanisms of focal activity. Ca-related functions are in red. (C) Determinants of atrial fibrillation maintaining re-entrant activity. Left: wavelength = refractory period × conduction velocity, determines size of functional re-entry circuits. Right: reduced wavelength allows more simultaneous circuits, making atrial fibrillation termination less likely. Wavelength can be reduced by decreased action potential duration. Ca-related functions that reduce wavelength include decreased I CaL and increased Ca-dependent K current (I KCa).
Re-entry maintenance depends on critical refractoriness and conduction conditions (Figure 1C). The 'leading circle' concept posits that functional re-entry establishes itself in the minimum sized circuit for re-entry maintenance, given by the distance ('wavelength') the impulse travels in one refractory period (RP): wavelength = RP × conduction velocity. When the number of circuits that the atria can contain is small (Figure 1C, left), re-entry is unstable and AF self-terminates. When the wavelength is reduced (e.g. when RP decreases), the circuits are smaller and more numerous, simultaneous termination of all circuits is unlikely, and AF is sustained (Figure 1C, right). Refractory period depends on action potential duration (APD). Action potential duration is reduced by decreasing inward current (ICaL), or by increasing outward K current. Recent genomic work suggests that a Ca-dependent K current plays an important role in AF, likely by controlling APD.
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