The Promise of Biological Pacemakers

Introduction

In modern day cardiology practice the insertion of electrical pacemaker devices is routine, with an estimated 434 devices being inserted per million people in the United States each year. Although the development of modern pacing devices revolutionised cardiology towards the end of the 20th century, electrical devices remain a palliation, rather than a cure, to an underlying disorder of cardiac rhythm. Thus in recent years the idea of a "biological" pacemaker, whereby artificial electrical components are replaced by cellular and genetic elements capable of producing intrinsic electrical activity, has taken several steps towards becoming a realistic therapeutic goal.

What advantages would such a development have over an already well-established method of treatment? Biological systems offer the promise of being more sensitive to the body’s autonomic nervous system, thus providing a more natural control of physiological heart rate compared to current rate sensing pacemakers. Implantation of biological systems into the correct anatomical location would also allow electrical conduction to mimic the heart’s intrinsic conduction system, such as the bundle of His, as closely as possible. Thirdly, many of downfalls of electrical pacemaker insertion, such as infection, battery replacement, and the induction of cardiac failure, could be reduced significantly, if not eliminated. For paediatric patients in particular, who face a lifetime of device changes, a biological pacemaker could prove to be a very effective cure.


What properties should a biological pacemaker have? Two main caveats would include; 1) the ability to initiate a cardiac impulse proximal enough in the conducting system to allow physiological depolarisation of the ventricles and 2) to have the ability to last as long as and be as reliable as current electrical pacemaker devices(Plotnikov, Sosunov et al. 2004).

Several different molecular approaches have been successfully shown to initiate spontaneous electrical activity in mammalian hearts, thus raising the initial question as to which method is the best. Of course, developing a suitable molecular pacing strategy will in part mean developing a suitable method of delivery. A final hurdle involves examining the efficacy, reliability and safety of the new technique. This article will review all the above areas with particular emphasis being made on outlining future challenges to be faced before this ambitious therapy can become a reality.

Background & Preliminary Work

Several different methods of developing an intrinsic pacing system at the molecular level have been attempted to date.

An initial approach to molecular manipulation of the pacing system of the heart was performed by Edelberg in 2001(Edelberg, Huang et al. 2001). By injecting plasmids encoding a beta-2 adrenergic receptor into the atria of pigs (at the site of earliest atrial potential found) faster mean heart rates were demonstrated in the days following plasmid than occurred in control animals. Unfortunately, such an increase in beta-adrenergic receptors also makes the heart more prone to arrhythmias(Rosen, Brink et al. 2004).

In 2002 Miake and colleagues demonstrated an alternative method of biological manipulation of the pacing system(Miake, Marban et al. 2002). Building on the fact that all cardiac cells possess pacemaker activity in the early embryonic heart, quiescent heart muscle cells were altered by adenoviral gene transfer of a dominant-negative form of Kir2. This gene family codes for an inward-rectifier potassium current (IKi) that normally hyperpolarises the cell membrane of ventricular myocytes and suppresses spontaneous electrical activity. Their simple paradigm proved true; by inhibiting the IK1 current spontaneous electrical activity was produced. However, as is common with all potassium channel modifications, this also resulted in a prolonged action potential which can increase the potential for arrhythmias.

More recent reports have aimed at altering the inward pacemaker current If, which flows only at diastolic potentials and thus should not affect the duration of the action-potential(Qu, Plotnikov et al. 2003). This can be done by overexpressing the HCN gene (hyperpolarization-activated cyclic nucleotide-gated channel), which allows inward sodium current and thus membrane depolarisation. By injecting adenoviral constructs containing the HCN2 gene, Rosen’s group was able to establish an If-based pacemaker in the atria of dogs(Qu, Plotnikov et al. 2003). This method has since been explored by other groups in more recent reports due to its improved safety profile (Kashiwakura, Cho et al. 2006; Tse, Xue et al. 2006).

Mesenchymal or stem cells with electrical activity have also been successfully transferred and shown to have spontaneous electrical activity in vivo(Xue, Cho et al. 2005). Xue et al. used a lentivirus vector to transfect human embryonic stem cells, which were then injected subepicardially into the left ventricular wall of guinea pig hearts. The integrated syncitium was responsive to the beta-adrenergic agonist isoproterenol, and optical mapping confirmed successful depolarisation from the site of myocardial injection. Rosen’s group have also loaded adult human mesenchymal stem cells with the HCN2 gene via electroporation, avoiding the need for viral vectors(Potapova, Plotnikov et al. 2004).

An alternative strategy could involve the use of fetal and/or neonatal cell transplants (Cai, Lin et al. 2006), or the use of human embryonic stem cells forced into a cardiogenic lineage. When injected into the myocardium of pigs with heart block, the cells have been shown to create an adequate pacemaker current and produce stable idioventricular rhythms(Kehat, Khimovich et al. 2004).

Once an optimal biological strategy has been formulated, cells must be delivered to the appropriate area. Naked DNA has been successfully transfected into the human heart, but it is technically difficult, inefficient and the effects are often very short lived. While more efficient, viral vectors also have problems in that they may cause allergic reactions. Furthermore, persistent viruses such as retrovirus may be complicated by the possibility of malignancy, while the safer adenovirus is less permanent. A third option involves the direct introduction of cells, either embryonic stem cells or human mesenchymal stem cells (hMSCs) which are derived from bone marrow. In fact, technically any cell type which expresses the HCN genes and cardiac connexin genes could serve as a cellular delivery system.

Of course a good delivery system must be accurate, and it is yet to be seen where in the intrinsic conducting system any cell therapy is best placed. Exactly how this is best achieved also remains to be seen; focal delivery with catheters and needles may be needed, or cells could be cultured on a matrix designed to adhere to cardiomyocytes. Most importantly, it will be necessary to prove that any implanted cells remain where they are inserted, and do not migrate to other areas of the heart, or indeed the body, where they may cause harm.

Finally, it is possible that implanted cells may be rejected, and that some form of immunosupression may become necessary. This leads to further obvious concerns about neoplastic transformation.

Future Challenges

In addition to the issues raised above, two main challenges emerge for the future: safety and cost. Introduction of any new electrical system into the heart could in theory precipitate arrhythmia, and the absence of any malignant arrhythmia will be a necessary precursor for any biological pacemaker. Furthermore, viral vectors have the ability to trigger neoplasia, and must only localise to the areas targeted if they are to be used comfortably.

When a reliable, accurate and efficient biological pacing system is formulated, the next step will be to test its efficiency in small animal models, before finally moving on to human clinical trials. In both these cases, initial introduction is likely to be in combination with traditional electrical systems, thus allowing a backup mechanism in the event of failure of the biological system.

Would a biological pacemaker be cost effective? It is far too early to answer this question. The field of gene therapy itself faces many challenges over the coming years; the development of a biological pacemaker is but one of them.

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