Prospects for Biological Cardiac Pacemaker Systems

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Prospects for Biological Cardiac Pacemaker Systems ARJANG RUHPARWAR and AXEL HAVERICH From the Department of Thoracic and Cardiovascular Surgery, Hannover Medical School, Hannover, Germany

The heart is endowed with specialized excitatory and conducting myocytes that are responsible for the generation and conduction of rhythmic impulses and contractions throughout the heart.1 If these cells are damaged by disease, the implantation of an artificial cardiac pacemaker is necessary to restore physiologic cardiac rhythm or create of the best physiologic alternative. Substantial data have been accumulated and indications have been well delineated for pacemaker implantation in the treatment of sinus node dysfunction and heart block. However, new indications have been suggested more recently, including: neurally mediated syncope, hypertrophic obstructive cardiomyopathy, congestive heart failure, and prevention of atrial fibrillation.2 As to the classical indications for cardiac pacemaker implantation mentioned previously, several limitations and problems have emerged during the past decades such as electrode fracture, damage to insulation, infection, reoperations for battery exchange, and vein thrombosis. In children, including premature babies with congenital or acquired arrhythmia such as AV block, initial size mismatch of the children, and growth affecting the position of leads and generators can pose a problem. Lead extraction has additional, potentially life-threatening risks such as perforation of the right ventricle, atrium, superior vena cava, or the subclavian vein that must be considered.3 The future of cardiac pacing may be in new directions: (1) optimization of existing pacemaker systems with more physiologic sensors as well as the design of new leads prolonging the life of generators and reducing the incidence of lead fracture and problems with insulation. New techniques for removing dysfunctional or infected leads need to be developed,4 (2) the second direction currently discussed at the basic science level is represented by concepts of biological repair. Here damaged tissue is replaced or repaired by cellular and genetic therapy using tissue engineering approaches, as applied in less complex tissues like cartilage, bone, or heart valves.5 Such procedures would represent efforts to become less dependent on artificial implants such as artificial cardiac pacemakers.

Address for reprints: Arjana Ruhparwar MD to Division of Thoracic and Cardiovascular Surgery, Carl-Neuberg-Str. 1,30625 Hannover, Germany. E-mail: [email protected] Received July 28, 2003; accepted August 6, 2003.

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Economic Considerations Based on the proportion of pulse generator models implanted in patients only in the United States, the maximum cost differential to the health care system is approximately $424 million/year comparing the devices with the shortest and greatest longevity.6 Considering the costs of pacemaker therapy, any improvement of the system has large economic implications, not to mention patient benefit. It is conceivable that the final therapeutic approach will be a combination of both artificial and biological systems such as pacemaker leads coated with pacemaker cells that interact with the recipient myocardium and therefore reduce the excitation threshold and thus energy consumption of the pacemaker (hybrid-technology). In this article we outline the various strategies that are being followed as a biological alternatives supplement to artificial cardiac pacemakers. Cell Therapy Recently we were able to show that transplanted fetal cardiomyocytes can function as a biological cardiac pacemaker.7 The aim of the study was to prove the hypothesis that by transplanting cardiomyocytes with a higher intrinsic rhythmic rate into the myocardium of the left ventricle, these cells could act as an ectopic pacemaker. Dissociated fetal canine atrial cardiomyocytes including sinus nodal cells were delivered into the free wall of the left ventricle of adult dogs. Importantly, after catheter ablation of the atrioventricular node (AV node), electrophysiological mapping studies revealed the ability of the engrafted cells to function as a cardiac pacemaker, because the main pace-making activity originated from the labeled transplantation site. After transplantation, to be regarded as a pacemaker, the cells needed to fulfill three electrophysiological criteria: (1) activation mapping ought to show the epicardially labeled site for fluoroscopy to be the source of the escape rhythm, (2) pacing at the injection site generates QRS complexes with morphology of the QRScomplexes of the escape rhythm without pacing, and (3) a QS pattern at the unipolar electrogram, indicating the beginning of the cardiac electrical impulse that moves away from the labeled site. In the cited study, all criteria were met by the engrafted cells (Fig. 1.). Moreover, the escape rhythm significantly increased after the administration of

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Figure 1. Mapping of the site of earliest activation of escape rhythm. (A) pace mapping performed from the endocardial site of the left ventricle (MAP bi) shows identical QRS pattern compared with the intrinsic rhythm (B). (C) activation mapping of the labeled site was 10 ms before QRS onset with a sharp QS morphology of unipolar electrogram (MAP bi and MAP uni), indicating the beginning of the cardiac electrical impulse which moves away from the labeled site.

isoproterenol (unpublished data), indicating positive chronotropic competence. The histological findings constituted a morphological correlate to the electrophysiological result, showing survival of grafted cells and formation of connexin 43 between donor and recipient cells. This molecule is the major constituent of cardiac gap junctions that enable transmission of electric excitation and with that contraction from cell to cell.8 These results represented the first observation of phenomena that indicate electrical and mechanical coupling between allogeneic donor and recipient cardiomyocytes in vivo. If cardiomyocyte engraftment proves to be of therapeutic value, for ethical and economic reasons the generation of autologous cardiomyocytes will be required. Possible approaches would be the generation of pluripotent embryonic or adult stem cells or achieving controlled proliferation of adult cardiomyocytes. Abi-Gerges et al. developed murine ES-cell derived cardiomyocytes using an α-myosin heavy chain (α-MHC) promoter driving an enhanced green fluorescent protein (eGFP) gene. Subsequent electrophysiological analysis of the cardiomyocytes, isolated by cell sorting, revealed an If pattern of action potentials in all resulting cells that is typical for Sinus nodal cardiomyocytes. The If action potential allows spontaneous depolarization of the cell with a shorter action potential than other areas of the myocardium.9 The result was surprising, as α-MHC is ubiquitous throughout the adult heart. This characteristic of the cells makes them possible cell can2070

didates for transplantation as a cardiac pacemaker which will have to be tested for pacemaker capability in vivo after transplantation in large animal models. The disadvantage of cell transplantation is the lack of available long-term data with respect to tracking of the fate of transplanted cells in terms of survival and arrythmogenecity. Additionally, the number of transplantable cells of the cardiac conduction system (CCS), regardless of their origin (fetal, adult, and stem cell derived) is limited. On the way to a biological cardiac pacemaker system it is therefore imperative to develop a method that allows transformation of a heterogenous population of cardiomyocytes into cells of the cardiac conductive tissue. So far there are no more known specific promoters for the cardiac conduction system that would enable us to genetically select cardiomyocytes by applying tissuespecific promoters driving antibiotic resistance in specific tissues or by using the expression of green fluorescent protein in certain cell types and subsequent cell sorting as published by Klug et al.10 and Muller et al.11 Gene Therapy Genetic therapy of arrhythmic disorders of the heart has been the subject of extensive studies of Eduardo Marban’s group. In a study published in 1996, Nuss et al.12 showed that the overexpression of potassium channels in cardiomyocytes of failing hearts in a canine model reverses the action potential prolongation that may provoke fatal arrhythmia often observed in patients with heart failure.13 Akhter et al. restored β-adrenoreceptor signaling in failing cardiomyocytes in a rabbit model by adenoviral gene transfer of human β 2 adrenoreceptors and transfer of a gene that inhibits β 2 -adrenoreceptor kinase.14 A recent study by Miake et al. of the same group represents the first successful gene therapy approach towards the generation of pacemaking activity in otherwise nonpacemaking adult cardiomyocytes using a guinea pig model.15 The investigators postulated latent pacemaker capability in nonconduction system cardiomyocytes. This potential ability is suppressed by the inward rectifier potassium current Ik1 encoded by the gene Kir2, which is not expressed in pacemaker cells. By specific inhibition of Ik1 below a certain level, spontaneous activity of cardiomyocytes was observed with resemblance to the action potential pattern of genuine pacemaker cells. Provided that a suitable vector for gene transfer with respect to durability and safety becomes available, this procedure represents a promising therapeutic approach for the treatment of bradycardiac arrhythmia.

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Hormone Therapy In a recent study16 Rentschler et al. showed that neuregulin-1, a growth factor that plays an important role in ventricular trabeculation during embryonic development,17 promotes formation of the murine cardiac conduction system (CCS) in an also recently identified CCS-lac-Z line of reporter mice.18 This was achieved by showing that neuregulin-1 induces ectopic expression of the lacZ conduction marker whithin a short period of 8.5 to 10.5 days postcoitum. If additional electrophysiological studies confirmed the pacemaking ability of the transformed cells, these results would indicate that the mentioned peptide possesses the capacity to cause significant transformation of a mixed population of embryonic cardiomyocytes into cells of the cardiac conduction system. Our own results indicate that neuregulin-I enhances the expression of connexin 40, a major constituent of gap junctions in the cardiac conduction system in embryonic cardiomyocytes (submitted for publication). The next step should be the use of this procedure in other transplantation cell candidates such as embryonic and adult stem cell-derived cardiomyocytes, whereby due to the lack of the transgenic animal model mentioned previously other parameters such as connexin 40 expression and electrophysiological studies ought to be measured and performed. In the future, all three possible procedures may be combined to achieve optimal results. In vitro treatment of cells and subsequent transplantation is one potential option.

Biological Safety Until this young field of research finds access to the clinic, the potential ability of engrafted cardiomyocytes or transfected genes to cause arrhythmia must be excluded in long-term studies with cardiac mapping experiments at various time points and with a large population of animals. Conclusion Given the level of sophistication of artificial cardiac pacemakers that are used today, from a clinician’s standpoint it may seem hard to imagine or predict whether biological cardiac pacemakers can comparably mimic normal cardiac physiology such as rate adaptation or atrioventricular synchrony. There are problems associated with implanted cardiac pacemaker systems as mentioned previously that cannot be ignored and justify the search for better alternatives. It is conceivable that the initial indication for biological cardiac pacemakers will be limited to children as “bridge to pacemaker” or to patients with chronic atrial fibrillation who do not require atrioventricular synchrony. For all other patients, cardiomyocyte transplant would have to occur at the junction of the atrium and ventricle to ensure coherent contraction of all cardiac chambers. However, given the complexity of processes in the physiology and pathophysiology of the cardiac rhythm, more genes and proteins and tissue engineering methods need to be identified and developed to achieve a differentiated therapeutic approach.

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10. Klug MG, Soonpaa MH, Koh GY, et al. Genetically selected cardiomyocytes from differentiating embryonic stem cells form stable intracardiac grafts. J Clin Invest 1996; 98:216–224. 11. Muller M, Fleischmann BK, Selbert S, et al. Selection of ventricularlike cardiomyocytes from ES cells in vitro. FASEB J 2000; 14:2540– 2548. 12. Nuss HB, Johns DC, Kaab S, et al. Reversal of potassium channel deficiency in cells from failing hearts by adenoviral gene transfer: A prototype for gene therapy for disorders of cardiac excitability and contractility. Gene Ther 1996; 10:900–912. 13. Zipes DP, Wellens HJJ. Sudden cardiac death. Circulation 1998; 98:2334–2351. 14. Akhter SA, Skaer CA, Kypson AP, et al. Restoration of βadrenergic signaling in failing cardiac ventricular cardiomyocytes via adenoviral–mediated gene transfer. Proc Natl Acad Sci 1997; 94:12100–12105. 15. Miake J, Marban E, Nuss HB. Gene therapy: Biological pacemaker created by gene transfer. Nature 2002; 419:132–133. 16. Rentschler S, Zander J, Meyers K, et al. Neuregulin-1 promotes formation of the murine cardiac conduction system. PNAS 2002; 16:10464–10469. 17. Meyer D, Birchmeir C. Multiple essential functions of Neuregulin in development. Nature 1995; 378:386–390. 18. Rentschler S, Vaidya DM, Tamaddon H et al. Visualization and functional characterization of the developing murine cardiac conduction system. Development 2001; 128:1785–1792.

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