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The Biological Pacemaker
In October 1958, the first fully internalized pacemaker was implanted at the Karolinska Institute in Sweden. Within hours, the unit ceased to function, or as Senning wrote in a retrospective account “at 2 am the pacemaker became silent.” When searching Medline with the key words “implantable pacemaker,” the first five citations dating from 1960 onward are case reports of various implants. The sixth publication, dated 1962, is entitled “Complications of an Implantable Cardiac Pacemaker.” Such is the history of the pacing field. Since that initial implant, millions of pacemakers have been implanted, saving lives and reducing or even eliminating symptoms. With these undeniable benefits of electronic pacemakers have also come the complications, occurring in 5% to 10% of implant procedures. Acute complications range from minor hematomas to more severe infections, pneumothoraxes, and cardiac perforations. Long-term management of pacemaker patients is complicated by device and lead failures and a requirement to change out the device when the battery expires. These limitations of device therapy have motivated the search for alternatives. One approach that has been widely publicized over the last few years is the idea of creating a “biological pacemaker” by either gene transfer or cell transplantation methods ( Table 23-1 ). In this chapter, I review the literature on this approach.
TABLE 23-1
Strategies to Replace Electronic Pacemakers
| Transgene [Reference] | Vector | Target | Results | Problems |
|---|---|---|---|---|
| β 2 Adrenergic receptor | Plasmid | Right atrium | 50% increase in heart rate | Effect only seen for 1 day, rhythm not mapped to gene transfer site |
| KCNJ2 GYG144-146AAA | Adenovirus | Whole heart | Observed ventricular automaticity | QT prolongation, no attempt to quantify rate or stability |
| HCN1 EVY235-237ΔΔΔ | Adenovirus | Left atrium | Average rate 64 bpm in sick sinus syndrome model | Study had only 2 animals per group, competing electronic pacemaker DDD 60 bpm limits analysis of biopacing rhythm, limited data |
| HCN2 wild type | Adenovirus | Left atrium | Escape rhythm during vagal arrest mapped to target area | Long pause before onset of escape rhythm, no visible phenotype during sinus rhythm, no data on durability |
| Adenovirus | LV left bundle branch | 54 bpm LV escape rhythm during vagal arrest, average HR 50-57 bpm after AV node ablation | Long pause before onset of escape rhythm, no visible phenotype during sinus rhythm (visible with AV block), required backup pacing 26%-34% of the time | |
| HCN2 E324A | Adenovirus | LV left bundle branch | Average HR 53 bpm after AV node ablation | Required VVI 45 bpm pacing 36% of the time |
| HCN212 | Adenovirus | LV left bundle branch | All animals developed VT | All animals developed VT |
| HCN4 wild type | Adenovirus | Right ventricle | Average HR 69 bpm after AV node ablation | No data on rate stability, animals only followed for 24 hr |
| ADCY6 | Adenovirus | Lateral left ventricle | Escape rhythm after AV node ablation | Burst ventricular pacing and isoproterenol required to induce rhythm. No longitudinal data |
| ADCY1 | Adenovirus | LV left bundle branch | Average HR 60 bpm after AV node ablation; median escape time 1.3 sec after overdrive pacing, electronic backup pacing needed 2% of the time | Baseline heart rate is less than intrinsic heart rate in dog; data limited to 5- to 7-day period after gene transfer, but overall few problems noted |
| HCN2 + ADCY1 | Adenovirus | LV left bundle branch | Average HR 100 bpm after AV node ablation; median escape time 1.1 sec after overdrive pacing, electronic backup pacing needed 1% of the time | Baseline heart rate is now coming close to the intrinsic heart rate in dog; still has a small requirement for electronic pacing, data limited to 5- to 7-day period after gene transfer |
| HCN2 + SCN4a | Adenovirus | LV left bundle branch | Average HR 80 bpm after AV node ablation; median escape time <1 sec after overdrive pacing, electronic backup pacing not used during peak gene expression | Baseline heart rate is less than intrinsic heart rate in dog; data limited to 5- to 7-day period after gene transfer, but overall few problems noted |
| HCN2 + KCNJ2 GYG144-146AAA | Adenovirus | LV left bundle branch | Average HR 94 bpm after AV node ablation; required electronic backup pacing 3% of the time at peak gene expression | Improved baseline heart rate but still less than intrinsic heart rate in dog, still has small requirement for electronic pacing, data limited to 5- to 7-day period after gene transfer |
| TBX18 | Adenovirus | Left ventricle | Average HR 78 after AV node ablation, required electronic backup pacing 1% of the time at peak gene expression | Baseline heart rate is less than intrinsic heart rate in pig, discrepancies in literature about stability of effect |
| Cell Type [Reference] | Manipulation | Target | Results | Problems |
| Fetal atrial myocytes | None | Left ventricle | Average HR 70 bpm after AV node ablation | Study had only 2 animals per group, long pause before stable biopacing, no long-term rhythm stability data, questionable feasibility for translation |
| Human embryonic stem cells | CM derivation and isolation of beating cells | Left ventricle | Average HR 59 bpm after AV node ablation | Stable rhythm seen in only half of the study animals, no long-term rhythm stability data |
| Human mesenchymal stem cells | HCN2 gene transfer | Left ventricle | Average HR 52-61 bpm after AV node ablation | Long pause before stable biopacing, after AV node ablation animals still had 25% of beats from VVI 35 electronic pacemaker |
| Guinea pig lung fibroblasts | HCN1 gene transfer, co-infusion with PEG5000 for cell fusion | Left ventricle | Observed ventricular escape beats during methacholine-induced sinus arrest | No stable biopacing |
| Cell Type [Reference] | Manipulation | Target | Results | Problems |
| Skeletal myoblasts | Tissue formation with cellagen and matrigel | AV grove | Functional AV bypass tract | Conduction not present for 8 weeks after transplant, lacks conduction properties of AV node, lacks insertion into His-Purkinje system for LV synchrony |
| Neonatal rat ventricular myocytes + endogenous cardiac stem cells | Tissue formation guided by magnetic beads | AV grove | Functional AV bypass tract | Lacks conduction properties of AV node, lacks insertion into His-Purkinje system for LV synchrony |
AV, Atrioventricular; CM, cardiomyocyte; HR, Heart rate; LV, left ventricular; VT, ventricular tachycardia.
Gene Therapy Approaches
Beta-2 Adrenergic Receptor Gene Transfer
The first attempt at genetic modulation of heart rate was a report by Edelberg et al who injected plasmids containing the beta-2 adrenergic receptor (β 2 -AR) into mouse right atria. They found expression of their vector in 81% of myocytes at the injection site, and they noted a heart rate of 550 beats per minute (bpm) for the active treatment group, which was significantly higher than the 370 bpm rate found in controls. The same investigators followed this original report with a subsequent pig study, where they did not quantify gene transfer but they reported a heart rate of 163 bpm for the β 2 -AR-receiving pigs relative to 127 bpm for controls. These studies showed promising results, but they also raised considerable questions. The investigators did not report the time course of heart rate increase for the mice, but in the pigs they found a statistically significant increase in heart rate only on the second day postinjection. The usual experience with plasmid-mediated gene transfer is that the effect persists for several weeks or even months after gene transfer. The transience of effect for the β 2 -AR experiments raises a concern that some toxic effect from expression of this gene may be a limiting factor. Additional concern is raised when considering possible mechanisms for the increase in heart rate. The mouse study did not target the specialized conducting system, and under ordinary circumstances atrial myocytes should not display automaticity. A potential mechanism for the heart rate increase from β 2 -AR expression in atrial myocytes is G s -mediated activation of adenylate cyclase causing an intracellular cascade that ultimately results in phosphorylation of the type 1 calcium channel and the ryanodine receptor. Increased activity of these calcium-handling proteins could cause automaticity by the calcium clock mechanism, but sustained increase in intracellular calcium would likely be toxic. The porcine study did target sinus node by injecting in the area electrically mapped as the earliest site of activation during sinus rhythm, but the extremely transient functional change in pigs suggests that toxicity may be a concern even in sinus nodal tissues. An additional concern from the figures demonstrating gene expression is that the green from the green fluorescent protein in controls and red from β 2 -AR immunostaining in the active-treatment group are apparently extracellular. These concerns should probably be addressed before translation of the β 2 -AR findings are contemplated.
I K1 Knock-Out
In the next illustration of heart rate modulation, Miake et al used a dominant negative mutation of the gene encoding the I K1 channel (KCNJ2 GYG144-146AAA) to create automaticity. The logic behind this strategy was that differences in I K1 between atrial and sinus nodal myocytes account for the relative instability of sinus nodal membrane potential, so that a deficit of I K1 would increase the probability of phase 4 depolarization and automaticity. The investigators admitted that their primary interest was in the electrophysiologic effects of I K1 on the action potential, and that they did not intentionally create pacemaking nodes. Their delivery method essentially scattered the transgene around the ventricular myocardium. Nonetheless, they reported finding evidence of ventricular automaticity in 40% of animals expressing the KCNJ2-AAA mutation. Further investigation found that at least 80% of endogenous I K1 needed to be eliminated for automaticity to occur.
No attempt was made to quantify rate or stability of the idioventricular rhythm in this report. Other concerns rising from the KCNJ2-AAA strategy include the repolarization delaying effects of gene expression and the possibility of atrioventricular (AV) nodal suppressing effects. The investigators reported some level of action potential prolongation and increased QT interval at all expression levels of the transgene, as opposed to the pacing phenotype that was only visible with 80% suppression of I K1 . Inspection of the very limited reported data also shows no apparent AV nodal conduction, even in areas where the atrial beat is timed far enough away from the preceding ventricular beat that AV nodal conduction should reasonably be expected. This finding is extrapolation from very limited data, and it should be assessed with more care if I K1 knock-out becomes part of a biopacing strategy. Overall, the findings with I K1 knock-out suggest that this may be a component of an overall biopacing strategy (with the above caveats).
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