Cardiac Pacemaker Dysfunction Arising From Different Studies of Ion Channel Remodeling in the Aging Rat Heart

Figures

• 

  FIGURE 1. (Ai,Aii) Action potentials computed from rat SAN myocyte model in adult (red) and older adult (green) conditions using the Aging Study-1 (left panels) and Aging Study-2 (right panels) datasets. Simulations were conducted by using the rat SAN cell model developed by Tao et al. (2011). (Bi–Gi,Bii–Gii) Underlying ionic channel currents and Ca2+-handling during APs: If, ICaL, INaCa, INaK, Ca2+ uptake and Ca2+ release.

• 

  FIGURE 2. Quantitative comparison between experimental and simulation data of the functional effects of aging on the pacemaking APs and their characteristics. (A) CL; (B) HR; (C) APD50; (D) dV/dtmax; (E) MDP; and (F) PA. Data for adult is shown in red, and from Aging Study-1 and -2 in green and blue, respectively. Experimental data with error bars, where available, are from Tellez et al. (2011); Hatch (2012), Huang et al. (2016), and Shinagawa et al. (2000), which were all from rat SAN cells.

• 

  FIGURE 3. Simulated role of reduced If and Ca2+ release from the SR in aging bradycardia. Changes in other ion-channel currents as reported by Tellez et al. (2011) in Aging Study-1 (right panels) and by Hatch (2012) and Huang et al. (2016) in Aging Study-2 (left panels) were omitted. (Ai,Aii) APs. (Bi,Bii) Ionic current profiles for If, and (Ci,Cii) for Ca2+ release, for adult (red) and older adult (green) conditions. (Di,Dii): Bar charts showing the simulated age-dependent relative change in HR for this case; data-points with error bars show the experimental HR reduction due to aging.

• 

  FIGURE 4. Effect of remodeled ICa,L, INaCa, and Ca2+ uptake on pacemaking APs (red: adult; green: older adult). Other ion channel changes, as seen by Tellez et al. (2011) in Aging Study-1 (right panels), and by Hatch (2012) in Aging Study-2 (left panels), were omitted in simulations. (Ai,Aii) APs. (Bi,Bii) ICa,L. (Ci,Cii) INaCa. (Di,Dii) Ca2+ uptake. (Ei,Eii) Relative HR and its reduction. Data-points with error bars show the experimental data.

• 

  FIGURE 5. (A) Simulated APs when the age-related remodeling of ICa,L alone (blue) was considered [other ion channel and Ca2+ handling changes, as seen by Tellez et al. (2011) in Aging Study-1 (right panels), and by Hatch (2012) in Aging Study-2 (left panels), were ignored]. The obtained APs were compared with those of adult (red) and those with all ion channel and Ca2+ handling remodeling were considered (green). (B) Relationship between CL and increase (positive direction) or decrease (negative direction) in gCaL. It demonstrates that CL increases with either an increased or a decreased gCaL compared to the reference value of 100%. MDP: the maximal diastolic membrane potential. TOP, the take-off potential at which a line drawn from the MDP along the diastolic depolarization time course intersects with a vertical line drawn from the AP overshoot.

• 

  FIGURE 6. APs for the adult and older adult conditions with the subset of changes to the ion-channel currents involved in Aging Study-1, namely IKr, IKs, Ito, ICa,T, and INaK (A). Panels (B–F) show the time traces for the relevant ion-channel currents, namely IKr, IKs, Ito, ICa,T and INaK in the adult and older adult conditions. (G) Illustrates the role of the individual remodeled ionic channels on CL values.

• 

  FIGURE 7. Diagrammatic representation to summarize the two ‘ways’ of remodeled ICa,L Investigated in this study and the mechanisms associated with each process.