- Email: [email protected]
Biological pacemakers: Ready for the clinic?
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] (2015) ]]]–]]]
Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
Editorial Commentary
Biological pacemakers: Ready for the clinic? Eugenio Cingolani, MDn Familial Arrhythmia Clinic, Cedars-Sinai Heart Institute, 127S. San Vicente Boulevard, Suite A3100, Los Angeles, CA 90448
Biological pacemakers (BioP) have been created by both gene and cell therapy in animal models of human disease. Cellbased BioP have been developed by delivery of spontaneously-beating embryoid bodies derived from embryonic stem cells (ESCs) into the myocardium, or human mesenchymal stem cells (hMSCs) “loaded” with pacemaker channel genes (HCN2) [1]. The translational potential of these two approaches has been limited for reasons described below. Somatic gene transfer with a single or combination of different ion channels, and more recently a human transcription factor (TBX18), have all been shown to create BioP activity in vivo [1–3]. The article by Boink et al. [4] summarizes the present state of BioP research, comparing studies from different investigators in the field and their potential to advancing to the clinic. The following important issues briefly discussed in the article merit further clarification when considering first-in-human BioP applications: (1) preferred biological agent, (2) patient selection, and (3) preferred delivery system.
Preferred biological agent As the authors acknowledged in their review, cell-based approaches have less robust pre-clinical data and are less likely to reach the clinic due to safety concerns such as arrhythmogenicity, teratoma formation, and migration from the injection site. Gene therapy approaches by either overexpression of pacemaker channel genes or somatic reprogramming by a single transcription factor (TBX18) are undoubtedly closer to clinical translation. Ion channel-based approaches are designed to produce artificial automaticity in normallyquiescent ventricular myocytes. The goal is not to create a faithful replica of a pacemaker cell, but rather to manipulate a
single component of the membrane channel repertoire so as to induce spontaneous firing in an excitable but normallyquiescent cell. Somatic reprogramming by TBX18, in contrast, actually converts ventricular myocytes to induce sinoatrial node (iSAN) cells that resemble endogenous SAN pacemaker cells. No single determinant of excitability is selectively overexpressed, the entire gene expression program is altered with resultant changes in fundamental cell physiology and morphology. Boink et al. [4] speculate that TBX18-induced reprogramming could theoretically increase the risk of arrhythmias. It should be noted, however, that no increase in arrhythmias was seen in either small- or large-animal studies [2,3]. The unparalleled extensive characterization performed in the largeanimal TBX18 pre-clinical study included continuous (real time) ECG telemetry recordings, repolarization parameters (both by ECG and monophasic action potentials), and programmed ventricular stimulation. Taken together, no evidence of increase in ventricular arrhythmias or arrhythmic risk (repolarization changes) was seen in TBX18-treated animals [2].
Patient selection for the first-in-human trial While the ultimate goal may be to replace the electronic pacemaker, it is important to be realistic in thinking about potential first-in-human applications. Device-related infections have been rising in the past decade not only due to an increase in device implantations, but also due to a higher incidence of bacterial infections in the US and worldwide, with significant associated morbidity and mortality [5,6]. Patients with device-related infections generally require complete removal of all hardware until they become infection-free on systemic antibiotics [7]. For those patients
Funding: Supported by NIH, USA/National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR000124, Cedars-Sinai Board of Governors Heart Stem Cell Center, USA. The author has indicated there are no conflicts of interest. n Tel.: þ1 310 248 6679; fax: þ1 310 423 6795. E-mail addresses: [email protected], [email protected] http://dx.doi.org/10.1016/j.tcm.2015.03.003 1050-1738/& 2015 Elsevier Inc. All rights reserved.
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who are pacemaker-dependent, a temporary transvenous pacing device needs to be utilized during antibiotic treatment to clear the infection, which typically requires 2 weeks. During this time, patients must be on continuous telemetric monitoring at bed rest. Moreover, the presence of an indwelling catheter can potentially undermine the ability of systemic antibiotics to clear the infection. A “hardware-free” temporary pacing alternative would be desirable in these patients to support the circulation in the interval after removal of the infected hardware and before implantation of a definitive permanent electronic pacemaker. An effective BioP could potentially provide temporary pacing, eliminating the need for indwelling hardware during antibiotic therapy and improving the outcomes and efficacy of such therapy by removing any possible nidus of infection associated with temporary transvenous leads. These patients desperately need a pacemaker, but have a contraindication to indwelling hardware (at least until the infection is cleared by hardware removal and antibiotic therapy). Other selected populations where electronic devices can be problematic or prohibitive include the pediatric population and fetuses afflicted with congenital heart block, a condition which is often fatal [8].
M
E D I C I N E
re fe r en ces
[1]
[2]
[3]
[4]
[5]
[6]
[7]
Preferred delivery system [8]
Although BioP have been successfully created in large animals by gene transfer, the delivery methods have been extremely invasive (open-chest or trans-arterial) approaches [9–11] limiting their potential for human translation. A minimally invasive delivery technique using right-sided catheterization has been recently optimized for the delivery of BioP, avoiding access to the arterial circulation with consequent risk of vascular complications or stroke [2,12]. The article by Boink et al. reviewed the different delivery alternatives favoring injection into the left bundle branch by a trans-arterial approach in those patients afflicted with infections, citing a recent editorial by Rosen [13] in which concerns were raised about injecting into “an infected chamber” in the setting of pacemaker-related infections. This betrays a misconception regarding the nature of pacemakerrelated infections, which are systemic in nature [14] and can affect both right and left-sided valves [15]; infection within the myocardium itself is exceedingly rare [16].
[9]
[10]
[11]
[12]
[13]
Conclusion
[14]
Ion channel-based and reprogramming-based BioP strategies have been carefully characterized in pre-clinical models of conduction disease. With appropriate attention to all the nuances, it seems likely that BioP strategies will soon make the transition from much hyped technology to actual clinical testing.
[15]
[16]
Acknowledgment The author would like to thank Dr. Eduardo Marbán for helpful discussions.
] (2015) ]]]–]]]
Cho HC, Marbán E. Biological therapies for cardiac arrhythmias: can genes and cells replace drugs and devices? Circ Res 2010;106:674–85. Hu YF, Dawkins JF, Cho HC, Marban E, Cingolani E. Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block. Sci Transl Med 2014;6:245ra294. Kapoor N, Liang W, Marban E, Cho HC. Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of TBX18. Nat Biotechnol 2013;31:54–62. Boink GJ, Christoffels VM, Robinson RB, Tan HL. The past, present, and future of pacemaker therapies. Trends Cardiovasc Med 2015 [this issue]. Chua JD, Wilkoff BL, Lee I, Juratli N, Longworth DL, Gordon SM. Diagnosis and management of infections involving implantable electrophysiologic cardiac devices. Ann Intern Med 2000;133:604–8. Cabell CH, Heidenreich PA, Chu VH, Moore CM, Stryjewski ME, Corey GR, et al. Increasing rates of cardiac device infections among medicare beneficiaries: 1990-1999. Am Heart J 2004;147:582–6. Sohail MR, Uslan DZ, Khan AH, Friedman PA, Hayes DL, Wilson WR, et al. Management and outcome of permanent pacemaker and implantable cardioverter-defibrillator infections. J Am Coll Cardiol 2007;49:1851–9. Ambrosi A, Wahren-Herlenius M. Congenital heart block: evidence for a pathogenic role of maternal autoantibodies. Arthritis Res Ther 2012;14:208. Bucchi A, Plotnikov AN, Shlapakova I, Danilo P Jr., Kryukova Y, Qu J, et al. Wild-type and mutant Hcn channels in a tandem biological-electronic cardiac pacemaker. Circulation 2006;114:992–9. Plotnikov AN, Sosunov EA, Qu J, Shlapakova IN, Anyukhovsky EP, Liu L, et al. Biological pacemaker implanted in canine left bundle branch provides ventricular escape rhythms that have physiologically acceptable rates. Circulation 2004;109:506–12. Boink GJ, Duan L, Nearing BD, Shlapakova IN, Sosunov EA, Anyukhovsky EP, et al. Hcn2/Skm1 gene transfer into canine left bundle branch induces stable, autonomically responsive biological pacing at physiological heart rates. J Am Coll Cardiol 2013;61:1192–201. Cingolani E, Yee K, Shehata M, Chugh SS, Marban E, Cho HC. Biological pacemaker created by percutaneous gene delivery via venous catheters in a porcine model of complete heart block. Heart Rhythm 2012. Rosen MR. Gene therapy and biological pacing. N Engl J Med 2014;371:1158–9. Baddour LM, Epstein AE, Erickson CC, Knight BP, Levison ME, Lockhart PB, et al. Update on cardiovascular implantable electronic device infections and their management: A scientific statement from the american heart association. Circulation 2010;121:458–77. Camus C, Leport C, Raffi F, Michelet C, Cartier F, Vilde JL. Sustained bacteremia in 26 patients with a permanent endocardial pacemaker: assessment of wire removal. Clin Infect Dis 1993;17:46–55. Al Soub H, Al Maslamani M, Al Khuwaiter J, El Deeb Y, Abu Khattab M. Myocardial abscess and bacteremia complicating mycobacterium fortuitum pacemaker infection: case report and review of the literature. Pediatr Infect Dis J 2009;28:1032–4.
E N D S I N
C
A R D I O V A S C U L A R
M
E D I C I N E
] (2015) ]]]–]]]
Available online at www.sciencedirect.com
www.elsevier.com/locate/tcm
Editorial Commentary
Biological pacemakers: Ready for the clinic? Eugenio Cingolani, MDn Familial Arrhythmia Clinic, Cedars-Sinai Heart Institute, 127S. San Vicente Boulevard, Suite A3100, Los Angeles, CA 90448
Biological pacemakers (BioP) have been created by both gene and cell therapy in animal models of human disease. Cellbased BioP have been developed by delivery of spontaneously-beating embryoid bodies derived from embryonic stem cells (ESCs) into the myocardium, or human mesenchymal stem cells (hMSCs) “loaded” with pacemaker channel genes (HCN2) [1]. The translational potential of these two approaches has been limited for reasons described below. Somatic gene transfer with a single or combination of different ion channels, and more recently a human transcription factor (TBX18), have all been shown to create BioP activity in vivo [1–3]. The article by Boink et al. [4] summarizes the present state of BioP research, comparing studies from different investigators in the field and their potential to advancing to the clinic. The following important issues briefly discussed in the article merit further clarification when considering first-in-human BioP applications: (1) preferred biological agent, (2) patient selection, and (3) preferred delivery system.
Preferred biological agent As the authors acknowledged in their review, cell-based approaches have less robust pre-clinical data and are less likely to reach the clinic due to safety concerns such as arrhythmogenicity, teratoma formation, and migration from the injection site. Gene therapy approaches by either overexpression of pacemaker channel genes or somatic reprogramming by a single transcription factor (TBX18) are undoubtedly closer to clinical translation. Ion channel-based approaches are designed to produce artificial automaticity in normallyquiescent ventricular myocytes. The goal is not to create a faithful replica of a pacemaker cell, but rather to manipulate a
single component of the membrane channel repertoire so as to induce spontaneous firing in an excitable but normallyquiescent cell. Somatic reprogramming by TBX18, in contrast, actually converts ventricular myocytes to induce sinoatrial node (iSAN) cells that resemble endogenous SAN pacemaker cells. No single determinant of excitability is selectively overexpressed, the entire gene expression program is altered with resultant changes in fundamental cell physiology and morphology. Boink et al. [4] speculate that TBX18-induced reprogramming could theoretically increase the risk of arrhythmias. It should be noted, however, that no increase in arrhythmias was seen in either small- or large-animal studies [2,3]. The unparalleled extensive characterization performed in the largeanimal TBX18 pre-clinical study included continuous (real time) ECG telemetry recordings, repolarization parameters (both by ECG and monophasic action potentials), and programmed ventricular stimulation. Taken together, no evidence of increase in ventricular arrhythmias or arrhythmic risk (repolarization changes) was seen in TBX18-treated animals [2].
Patient selection for the first-in-human trial While the ultimate goal may be to replace the electronic pacemaker, it is important to be realistic in thinking about potential first-in-human applications. Device-related infections have been rising in the past decade not only due to an increase in device implantations, but also due to a higher incidence of bacterial infections in the US and worldwide, with significant associated morbidity and mortality [5,6]. Patients with device-related infections generally require complete removal of all hardware until they become infection-free on systemic antibiotics [7]. For those patients
Funding: Supported by NIH, USA/National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR000124, Cedars-Sinai Board of Governors Heart Stem Cell Center, USA. The author has indicated there are no conflicts of interest. n Tel.: þ1 310 248 6679; fax: þ1 310 423 6795. E-mail addresses: [email protected], [email protected] http://dx.doi.org/10.1016/j.tcm.2015.03.003 1050-1738/& 2015 Elsevier Inc. All rights reserved.
2
TR
E N D S I N
C
A R D I O V A S C U L A R
who are pacemaker-dependent, a temporary transvenous pacing device needs to be utilized during antibiotic treatment to clear the infection, which typically requires 2 weeks. During this time, patients must be on continuous telemetric monitoring at bed rest. Moreover, the presence of an indwelling catheter can potentially undermine the ability of systemic antibiotics to clear the infection. A “hardware-free” temporary pacing alternative would be desirable in these patients to support the circulation in the interval after removal of the infected hardware and before implantation of a definitive permanent electronic pacemaker. An effective BioP could potentially provide temporary pacing, eliminating the need for indwelling hardware during antibiotic therapy and improving the outcomes and efficacy of such therapy by removing any possible nidus of infection associated with temporary transvenous leads. These patients desperately need a pacemaker, but have a contraindication to indwelling hardware (at least until the infection is cleared by hardware removal and antibiotic therapy). Other selected populations where electronic devices can be problematic or prohibitive include the pediatric population and fetuses afflicted with congenital heart block, a condition which is often fatal [8].
M
E D I C I N E
re fe r en ces
[1]
[2]
[3]
[4]
[5]
[6]
[7]
Preferred delivery system [8]
Although BioP have been successfully created in large animals by gene transfer, the delivery methods have been extremely invasive (open-chest or trans-arterial) approaches [9–11] limiting their potential for human translation. A minimally invasive delivery technique using right-sided catheterization has been recently optimized for the delivery of BioP, avoiding access to the arterial circulation with consequent risk of vascular complications or stroke [2,12]. The article by Boink et al. reviewed the different delivery alternatives favoring injection into the left bundle branch by a trans-arterial approach in those patients afflicted with infections, citing a recent editorial by Rosen [13] in which concerns were raised about injecting into “an infected chamber” in the setting of pacemaker-related infections. This betrays a misconception regarding the nature of pacemakerrelated infections, which are systemic in nature [14] and can affect both right and left-sided valves [15]; infection within the myocardium itself is exceedingly rare [16].
[9]
[10]
[11]
[12]
[13]
Conclusion
[14]
Ion channel-based and reprogramming-based BioP strategies have been carefully characterized in pre-clinical models of conduction disease. With appropriate attention to all the nuances, it seems likely that BioP strategies will soon make the transition from much hyped technology to actual clinical testing.
[15]
[16]
Acknowledgment The author would like to thank Dr. Eduardo Marbán for helpful discussions.
] (2015) ]]]–]]]
Cho HC, Marbán E. Biological therapies for cardiac arrhythmias: can genes and cells replace drugs and devices? Circ Res 2010;106:674–85. Hu YF, Dawkins JF, Cho HC, Marban E, Cingolani E. Biological pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block. Sci Transl Med 2014;6:245ra294. Kapoor N, Liang W, Marban E, Cho HC. Direct conversion of quiescent cardiomyocytes to pacemaker cells by expression of TBX18. Nat Biotechnol 2013;31:54–62. Boink GJ, Christoffels VM, Robinson RB, Tan HL. The past, present, and future of pacemaker therapies. Trends Cardiovasc Med 2015 [this issue]. Chua JD, Wilkoff BL, Lee I, Juratli N, Longworth DL, Gordon SM. Diagnosis and management of infections involving implantable electrophysiologic cardiac devices. Ann Intern Med 2000;133:604–8. Cabell CH, Heidenreich PA, Chu VH, Moore CM, Stryjewski ME, Corey GR, et al. Increasing rates of cardiac device infections among medicare beneficiaries: 1990-1999. Am Heart J 2004;147:582–6. Sohail MR, Uslan DZ, Khan AH, Friedman PA, Hayes DL, Wilson WR, et al. Management and outcome of permanent pacemaker and implantable cardioverter-defibrillator infections. J Am Coll Cardiol 2007;49:1851–9. Ambrosi A, Wahren-Herlenius M. Congenital heart block: evidence for a pathogenic role of maternal autoantibodies. Arthritis Res Ther 2012;14:208. Bucchi A, Plotnikov AN, Shlapakova I, Danilo P Jr., Kryukova Y, Qu J, et al. Wild-type and mutant Hcn channels in a tandem biological-electronic cardiac pacemaker. Circulation 2006;114:992–9. Plotnikov AN, Sosunov EA, Qu J, Shlapakova IN, Anyukhovsky EP, Liu L, et al. Biological pacemaker implanted in canine left bundle branch provides ventricular escape rhythms that have physiologically acceptable rates. Circulation 2004;109:506–12. Boink GJ, Duan L, Nearing BD, Shlapakova IN, Sosunov EA, Anyukhovsky EP, et al. Hcn2/Skm1 gene transfer into canine left bundle branch induces stable, autonomically responsive biological pacing at physiological heart rates. J Am Coll Cardiol 2013;61:1192–201. Cingolani E, Yee K, Shehata M, Chugh SS, Marban E, Cho HC. Biological pacemaker created by percutaneous gene delivery via venous catheters in a porcine model of complete heart block. Heart Rhythm 2012. Rosen MR. Gene therapy and biological pacing. N Engl J Med 2014;371:1158–9. Baddour LM, Epstein AE, Erickson CC, Knight BP, Levison ME, Lockhart PB, et al. Update on cardiovascular implantable electronic device infections and their management: A scientific statement from the american heart association. Circulation 2010;121:458–77. Camus C, Leport C, Raffi F, Michelet C, Cartier F, Vilde JL. Sustained bacteremia in 26 patients with a permanent endocardial pacemaker: assessment of wire removal. Clin Infect Dis 1993;17:46–55. Al Soub H, Al Maslamani M, Al Khuwaiter J, El Deeb Y, Abu Khattab M. Myocardial abscess and bacteremia complicating mycobacterium fortuitum pacemaker infection: case report and review of the literature. Pediatr Infect Dis J 2009;28:1032–4.