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. 2011;20(11-12):1907-14.
doi: 10.3727/096368911X565038. Epub 2011 Mar 8.

Implantation of sinoatrial node cells into canine right ventricle: biological pacing appears limited by the substrate

Hao Zhang  1 , David H Lau, Iryna N Shlapakova, Xin Zhao, Peter Danilo, Richard B Robinson, Ira S Cohen, Dan Qu, Zhiyun Xu, Michael R Rosen
Affiliations

Implantation of sinoatrial node cells into canine right ventricle: biological pacing appears limited by the substrate

Hao Zhang et al. Cell Transplant. 2011.

Abstract

Biological pacing has been proposed as a physiologic counterpart to electronic pacing, and the sinoatrial node (SAN) is the general standard for biological pacemakers. We tested the expression of SAN pacemaker cell activity when implanted autologously in the right ventricle (RV). We induced complete heart block and implanted electronic pacemakers in the RV of adult mongrel dogs. Autologous SAN cells isolated enzymatically were studied by patch clamp to confirm SAN identity. SAN cells (400,000) were injected into the RV subepicardial free wall and dogs were monitored for 2 weeks. Pacemaker function was assessed by overdrive pacing and IV epinephrine challenge. SAN cells expressed a time-dependent inward current (I(f)) activating on hyperpolarization: density = 4.3 ± 0.6 pA/pF at -105 mV. Four of the six dogs demonstrated >50% of beats originating from the implant site at 24 h. Biological pacemaker rates on days 7-14 = 45-55 bpm and post-overdrive escape times = 1.5-2.5 s. Brisk catecholamine responsiveness occurred. Dogs implanted with autologous SAN cells manifest biological pacing properties dissimilar from those of the anatomic SAN. This highlights the importance of cell and substrate interaction in generating biological pacemaker function.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(A) Dissociated sinoatrial node (SAN) cell in recording chamber before and during patch electrode impalement. Dissociated SAN cells were spindle shaped and more than 80% exhibited spontaneous rhythms in calcium-free enzyme solution. Only single dissociated SAN cells with contractile activity were selected for microelectrode study. (B) Dissociated SAN cells manifest spontaneous action potentials. (C) Representative records from a dissociated SAN cell during the voltage clamp protocol. (D) Summary data: SAN cells exhibit robust If (density 4.3 ± 0.6 pA/pF at −105 mV).
Figure 2
Figure 2
Upper panel: Representative surface electrocardiography (ECGs) from a dog following autologous SAN cells transplant. The “Implant” ECG shows the pace-mapped surface ECG obtained by electronically pacing the implant site during surgery. ECGs were then recorded over a 14-day period. Shown are ECGs recorded on day 4, 9, and 14. Note that the QRS axis and configuration are similar to the QRS recorded during surgery suggesting the ventricular pacemaker activity is originating from the SAN cells’ implant site. Paper speed = 25 mm/s; 1 cm = 1 mV. Lower panels: Escape times after overdrive pacing (A), escape rates (B), percent of electronically paced beats (C), and percent of beats that pace-mapped to the injection site (D) for the 4 dogs showing >50% of beats mapping to the injection site on days 1–2. Shown here are data from days 1, 7, and 14 as means ± SD. ANOVA shows no differences across days. See text for discussion.
Figure 3
Figure 3
Pace-mapping data from one dog using six-lead ECG. (A) Recording during electronic pacing using a bipolar electrode placed epicardially at the site of cell administration. (B) Recording 2 days later from the awake animal of biological pacemaker-induced rhythm. Note comparability of complexes in (A) and (B).
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