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Ion Channels in the Heart

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ABSTRACT

Optimal cardiac function depends on proper timing of excitation and contraction in various regions of the heart, as well as on appropriate heart rate. This is accomplished via specialized electrical properties of various components of the system, including the sinoatrial node, atria, atrioventricular node, His‐Purkinje system, and ventricles. Here we review the major regionally determined electrical properties of these cardiac regions and present the available data regarding the molecular and ionic bases of regional cardiac function and dysfunction. Understanding these differences is of fundamental importance for the investigation of arrhythmia mechanisms and pharmacotherapy. © 2015 American Physiological Society. Compr Physiol 5:1423‐1464, 2015.

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Figure 1. Figure 1. Regional heterogeneity of the electrical properties of the heart. (A) Schematic of different regions of the human heart and the corresponding (B) AP waveforms (below is a representative lead I ECG). (C) Overview of review organization. (D) Ion channel and regulatory protein gene expression are compared between corresponding regions of the heart [modified from (178) with permission]. The genes listed are significantly more strongly expressed in the region listed relative to the reference region indicated. SVC, superior vena cava; SAN, sinoatrial node; RA, right atrium; LA, left atrium; IVC, interventricular septum; AVN, atrioventricular node; RV, right ventricle; LV, left ventricle.
Figure 2. Figure 2. SAN structure and function. (A) Schematic showing endocardial view of SAN area (location corresponds to box around SAN in Fig. 1A). Approximate area of functional conduction block is shown in gray. (B) Transmural view of SAN showing organization of central and peripherial SAN cells. Redrawn from (74) with permission. (C) Example APs and ionic currents from central and peripheral SAN cells. Redrawn from (375) with permission. (D) Ivabradine, an If blocker, slows SAN beat rate via slowing the rate of diastolic depolarization [with permission from (85)]. (E) Slowing of SAN beat rate also occurs with ryanodine, a blocker of RyR Ca2+ release, demonstrating the importance of the Ca2+ clock in contributing to normal SAN pacemaking [with permission from (64)]. CT, crista terminalis; CTL, control; Endo, endocardium; Epi, epicardium; IVC, inferior vena cava; RA, right atrium; RYAN, ryanodine; SEP, interatrial septum; SVC, superior vena cava.
Figure 3. Figure 3. Atrial myocyte function and dysfunction. AP, CaT, and major underlying ionic currents simulated with computational models of human atrial sinus rhythm (black) and AF (red) myocytes. Modified, with permission, from (196).
Figure 4. Figure 4. Heterogeneity of atrial electrophysiology. Three different outward current patterns in human atrial myocytes confer distinct AP shape and properties [(redrawn from (541) with permission].
Figure 5. Figure 5. Ionic mechanisms of ectopic activity and reentry. Left: cellular mechanisms of early and delayed afterdepolarizations and cardiac cell automaticity. Right: mechanisms of reentry, redrawn with permission from (531).
Figure 6. Figure 6. AVN structure and function. (A) Schematic showing endocardial view of AVN area (location corresponds to box around AVN in Fig. 1A). Redrawn from (232) with permission. (B) Example AN‐like AP. (C) Example N‐like AP. (D) Example NH‐like AP. Panels B‐D redrawn with permission from (342). AN, atrio‐nodal; CFB, central fibrous body; CN, compact node; CS, coronary sinus; HIS, penetrating His bundle; IAS, interatrial septum; INE, inferior nodal extension; N, nodal; NH, nodal‐His; TT, tendon of Todaro; TV, tricuspid valve; TZ, transitional zone; VS, ventricular septum.
Figure 7. Figure 7. Ventricular AP and ion currents. Depicted in this figure are (A) simulated human ventricular AP (black) and CaT (blue). (B) The major depolarizing Na+ (INa, red) and Ca2+ (ICaL, blue) currents (inset shows the different time‐course of activation and current decay), (C) the major repolarizing K+ currents (Ito, purple; IKr, brown; IKs, black, and IK1, green), and (D) Na+/Ca2+ exchange (INCX, turquoise) and Na+/K+ pump (INKA, black) currents during a ventricular AP are shown (194). Redrawn, with permission, from (192).
Figure 8. Figure 8. Species Differences in ventricular AP waveforms and drug response. (A) Representative traces of ECG recordings from lead I of a human and mouse are depicted [redrawn, with permission, from (251)]. Inset shows a single P‐S interval of the mouse ECG. (B) A rabbit ventricular AP (i) is shortened and loses its plateau (ii‐v) as mouse K+ currents are integrated. (C) The simulated IV relations of mouse Ito, Ik,slow, Iss, and IK1 that are added to the rabbit AP simulation are plotted [reprinted, with permission, from (339)]. (D) Shown are ventricular AP recordings of IKr or IKs block in human, dog, or guinea pig. The figure demonstrates the species‐specific sensitivity to drug block and changes in AP morphology [reprinted, with permission, from (416)].
Figure 9. Figure 9. Multiple mechanisms underlie ventricular arrhythmia in HF. (A) Sustained focal ventricular tachycardia (VT) induced following local sympathetic stimulation in a normal rabbit heart pretreated with 50 μmol/L BaCl2 to reduce IK1 and 200 μmol/L caffeine to sensitize RyR. When applied simultaneously, a highly arrhythmogenic phenotype was observed, but neither condition alone (BaCl2 or caffeine) produced an increase in arrhythmic events (not shown). (B) Activation map demonstrating the focal origin and spread of propagation of a single beat of VT. (C) Superimposed Em (black) and [Ca2+]i (red) traces from the origin of focal activity showing diastolic Em and [Ca2+]i elevation [reprinted, with permission, from (343)].


Figure 1. Regional heterogeneity of the electrical properties of the heart. (A) Schematic of different regions of the human heart and the corresponding (B) AP waveforms (below is a representative lead I ECG). (C) Overview of review organization. (D) Ion channel and regulatory protein gene expression are compared between corresponding regions of the heart [modified from (178) with permission]. The genes listed are significantly more strongly expressed in the region listed relative to the reference region indicated. SVC, superior vena cava; SAN, sinoatrial node; RA, right atrium; LA, left atrium; IVC, interventricular septum; AVN, atrioventricular node; RV, right ventricle; LV, left ventricle.


Figure 2. SAN structure and function. (A) Schematic showing endocardial view of SAN area (location corresponds to box around SAN in Fig. 1A). Approximate area of functional conduction block is shown in gray. (B) Transmural view of SAN showing organization of central and peripherial SAN cells. Redrawn from (74) with permission. (C) Example APs and ionic currents from central and peripheral SAN cells. Redrawn from (375) with permission. (D) Ivabradine, an If blocker, slows SAN beat rate via slowing the rate of diastolic depolarization [with permission from (85)]. (E) Slowing of SAN beat rate also occurs with ryanodine, a blocker of RyR Ca2+ release, demonstrating the importance of the Ca2+ clock in contributing to normal SAN pacemaking [with permission from (64)]. CT, crista terminalis; CTL, control; Endo, endocardium; Epi, epicardium; IVC, inferior vena cava; RA, right atrium; RYAN, ryanodine; SEP, interatrial septum; SVC, superior vena cava.


Figure 3. Atrial myocyte function and dysfunction. AP, CaT, and major underlying ionic currents simulated with computational models of human atrial sinus rhythm (black) and AF (red) myocytes. Modified, with permission, from (196).


Figure 4. Heterogeneity of atrial electrophysiology. Three different outward current patterns in human atrial myocytes confer distinct AP shape and properties [(redrawn from (541) with permission].


Figure 5. Ionic mechanisms of ectopic activity and reentry. Left: cellular mechanisms of early and delayed afterdepolarizations and cardiac cell automaticity. Right: mechanisms of reentry, redrawn with permission from (531).


Figure 6. AVN structure and function. (A) Schematic showing endocardial view of AVN area (location corresponds to box around AVN in Fig. 1A). Redrawn from (232) with permission. (B) Example AN‐like AP. (C) Example N‐like AP. (D) Example NH‐like AP. Panels B‐D redrawn with permission from (342). AN, atrio‐nodal; CFB, central fibrous body; CN, compact node; CS, coronary sinus; HIS, penetrating His bundle; IAS, interatrial septum; INE, inferior nodal extension; N, nodal; NH, nodal‐His; TT, tendon of Todaro; TV, tricuspid valve; TZ, transitional zone; VS, ventricular septum.


Figure 7. Ventricular AP and ion currents. Depicted in this figure are (A) simulated human ventricular AP (black) and CaT (blue). (B) The major depolarizing Na+ (INa, red) and Ca2+ (ICaL, blue) currents (inset shows the different time‐course of activation and current decay), (C) the major repolarizing K+ currents (Ito, purple; IKr, brown; IKs, black, and IK1, green), and (D) Na+/Ca2+ exchange (INCX, turquoise) and Na+/K+ pump (INKA, black) currents during a ventricular AP are shown (194). Redrawn, with permission, from (192).


Figure 8. Species Differences in ventricular AP waveforms and drug response. (A) Representative traces of ECG recordings from lead I of a human and mouse are depicted [redrawn, with permission, from (251)]. Inset shows a single P‐S interval of the mouse ECG. (B) A rabbit ventricular AP (i) is shortened and loses its plateau (ii‐v) as mouse K+ currents are integrated. (C) The simulated IV relations of mouse Ito, Ik,slow, Iss, and IK1 that are added to the rabbit AP simulation are plotted [reprinted, with permission, from (339)]. (D) Shown are ventricular AP recordings of IKr or IKs block in human, dog, or guinea pig. The figure demonstrates the species‐specific sensitivity to drug block and changes in AP morphology [reprinted, with permission, from (416)].


Figure 9. Multiple mechanisms underlie ventricular arrhythmia in HF. (A) Sustained focal ventricular tachycardia (VT) induced following local sympathetic stimulation in a normal rabbit heart pretreated with 50 μmol/L BaCl2 to reduce IK1 and 200 μmol/L caffeine to sensitize RyR. When applied simultaneously, a highly arrhythmogenic phenotype was observed, but neither condition alone (BaCl2 or caffeine) produced an increase in arrhythmic events (not shown). (B) Activation map demonstrating the focal origin and spread of propagation of a single beat of VT. (C) Superimposed Em (black) and [Ca2+]i (red) traces from the origin of focal activity showing diastolic Em and [Ca2+]i elevation [reprinted, with permission, from (343)].
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Daniel C. Bartos, Eleonora Grandi, Crystal M. Ripplinger. Ion Channels in the Heart . Compr Physiol 2015, 5: 1423-1464. doi: 10.1002/cphy.c140069