Biological Pacemaker

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  • Physiological and Other Biological Pacemakers
    Electrical Diseases of the Heart, 2020
    Co-Authors: Michael R. Rosen, Ira S. Cohen, Peter R. Brink, Richard B Robinson
    Abstract:

    Physiological pacemaking in the heart is the province of the sinus node, in which a family of ionic currents contributes to the Pacemaker potential. Of paramount importance in initiating Pacemaker function is I f, an inward current carried by sodium through a family of channels that is hyperpolarization activated and cyclic nucleotide gated (HCN channels). In many settings where physiological pacemaking fails, therapy involves electronic pacing. Because of shortcomings in this otherwise excellent technology, there has been a search for Biological alternatives in which either gene or cell therapy is used to decrease outward current or increase inward current to provide Pacemaker function. The various technologies used will be summarized as well as directions for optimizing Biological Pacemaker function and for using them in tandem with electronic units.

  • Gene therapy for restoring heart rhythm.
    Journal of Cardiovascular Pharmacology and Therapeutics, 2014
    Co-Authors: Gerard J.j. Boink, Richard B Robinson
    Abstract:

    Efforts to use gene therapy to create a Biological Pacemaker as an adjunct or replacement of electronic Pacemakers have been ongoing for about 15 years. For the past decade, most of these efforts have focused on the hyperpolarization-activated cyclic nucleotide gated-(HCN) gene family of channels alone or in combination with other genes. The HCN gene family is the molecular correlate of the cardiac Pacemaker current, If. It is a suitable basis for a Biological Pacemaker because it generates a depolarizing inward current primarily during diastole and is directly regulated by cyclic adenosine monophosphate (cAMP), thereby incorpor- ating autonomic responsiveness. However, Biological Pacemakers based either on native HCN channels or on mutated HCN channels designed to optimize biophysical characteristics have failed to attain the desired basal and maximal physiological heart rates in large animals. More recent work has explored dual gene therapy approaches, combining an HCN variant with another gene to reduce outward current, increase an additional inward current, or enhance cAMP synthesis. Several of these dual gene therapy approaches have demonstrated appropriate basal and maximal heart rates with little or no reliance on a backup electronic Pacemaker during the period of study. Future research, besides examining the efficacy of other gene combinations, will need to consider the additional issues of safety and persistence of the viral vectors often used to deliver these genes to a specific cardiac region.

  • The road to Biological pacing
    Nature Reviews Cardiology, 2011
    Co-Authors: Michael R. Rosen, Richard B Robinson, Peter R. Brink, Ira S. Cohen
    Abstract:

    The field of Biological pacing is entering its second decade of active investigation. The inception of this area of study was serendipitous, deriving largely from observations made by several teams of investigators, whose common interest was to understand the mechanisms governing cardiac impulse initiation. Research directions taken have fallen under the broad headings of gene therapy and cell therapy, and biomaterials research has also begun to enter the field. In this Review, we revisit certain milestones achieved through the construction of a 'roadmap' in Biological pacing. Whether the end result will be a clinically applicable Biological Pacemaker is still uncertain. However, promising constructs that achieve physiologically relevant heart rates and good autonomic responsiveness are now available, and proof of principle studies are giving way to translation to large-animal models in long-term studies. Provided that interest in the field continues, the next decade should see either Biological Pacemakers become a clinical reality or the improvement of electronic Pacemakers to a point where the Biological approach is no longer a viable alternative. Biological pacing is a disruptive technology that aims first to improve upon, then to supplement and, eventually, to replace electronic pacing Biological pacing utilizes the tools of gene and cell therapy to introduce Pacemaker function to preselected regions of the heart Gene therapy focuses on delivery via viral vectors; whereas cell therapy uses either mesenchymal stem cells as delivery systems or cells with sinoatrial node-like properties derived from pluripotent stem cells Proof-of-concept has been achieved in studies of large animals in complete heart block and, in some instances, sinoatrial node dysfunction Substantial barriers remain to be overcome before clinical trials of Biological pacing can be begun, but the field is advancing steadily towards this goal The field of Biological cardiac pacing, which aims to improve upon, supplement and, eventually, to replace electronic pacing has come a long way since its inception more than a decade ago. Broadly, research has been focused on gene and cell therapy. In this Review, Rosen and colleagues highlight milestones achieved through the construction of a 'roadmap' in Biological pacing, and discuss the barriers that remain to be overcome before clinical trials of Biological pacing can be begun.

  • Implantation of sinoatrial node cells into canine right ventricle: Biological pacing appears limited by the substrate.
    Cell Transplantation, 2011
    Co-Authors: Hao Zhang, Richard B Robinson, Iryna N Shlapakova, Peter Danilo, Xin Zhao, Ira S. Cohen, Dan Qu, Zhiyun Xu, Michael R. Rosen
    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.

  • Bradyarrhythmia Therapies: The Creation of Biological Pacemakers and Restoring Atrioventricular Node Function
    Regenerating the Heart, 2011
    Co-Authors: Richard B Robinson
    Abstract:

    In the USA, over 300,000 electronic Pacemakers are implanted annually to treat slow heart rates resulting from abnormal sinus or atrioventricular (AV) node function. Although life-saving, limitations and problems with this hardware-based approach have led to interest in using gene and cell delivery methods to develop purely Biological based therapies. The goal in creating a Biological Pacemaker or AV bypass is not to replicate the sinus or AV nodes at a cellular or molecular level, but rather to recreate their functionality. There has been more research on Biological Pacemakers than on AV bypasses, and the former has explored both implantation of endogenously automatic cells and genetic engineering methods, with the latter involving either direct gene delivery or gene delivery to stem cells that are subsequently implanted into the myocardium. This makes use of all the tools of bioinformatics and molecular biology to engineer custom channels with distinct biophysical properties that may be best suited for a specific patient population or implant site. Although various gene products have been targeted as the basis of a Biological Pacemaker, most recent efforts have focused on the HCN gene family of Pacemaker current. These channels open on hyperpolarization, so they contribute current largely during diastole and have minimal impact on action potential duration. Further, these channels directly bind and respond to the adrenergic second messenger cyclic AMP, so autonomic responsiveness is integral to an HCN-based Biological Pacemaker. Although proof of principle has been demonstrated by a number of laboratories in several model systems, numerous challenges remain to achieve physiologically appropriate rates with sufficient robustness. Before clinical trials can begin, critical issues of safety and persistence of function must first be addressed in long-term animal studies. Even then, the appropriate patient population will be limited until a Biological AV bypass is also developed to ensure AV synchrony. However, the possibility of implanting a Biologically based bypass tract, perhaps containing a proximal Pacemaker, is compelling, and provides the continuing motivation driving these research efforts.

Stephanie Protze - One of the best experts on this subject based on the ideXlab platform.

Gordon Keller - One of the best experts on this subject based on the ideXlab platform.

Eduardo Marbán - One of the best experts on this subject based on the ideXlab platform.

  • Abstract 16405: Long-Term Biological Pacemaker Activity Created by Percutaneous TBX18 Gene Transfer
    Circulation, 2014
    Co-Authors: Yu-feng Hu, James Dawkins, Eduardo Marbán, Eugenio Cingolani
    Abstract:

    Background: Minimally-invasive TBX18 gene transfer creates physiologically-relevant Biological Pacemaker (BioP) activity for at least 2 weeks in pigs with complete heart block, providing evidence for therapeutic somatic reprogramming in a clinically-relevant disease model (Hu et al, Sci Trans Med 2014). It remains unknown how long Biological Pacemaker activity is maintained after TBX18 gene transfer. Hypothesis: We tested whether TBX18 gene transfer could create sustained BioP activity beyond two weeks. Methods: Adenoviral vectors expressing either TBX18 (n=3) or GFP (n=2) as a control were delivered into the high right ventricular septum via injection catheters (NOGA™ Myostar). Rate and rhythm were followed continuously for one month by implanted telemetry, and backup device utilization was quantified by serial Pacemaker interrogations. Physical activity was measured by a built-in accelerometer. Results: BioP activity was evident in TBX18 -transduced animals and persisted at least for 4 weeks. At week 4, maximal heart rate (HR,101±8 vs. 65±3bpm, p

  • abstract 16405 long term Biological Pacemaker activity created by percutaneous tbx18 gene transfer
    Circulation, 2014
    Co-Authors: Yu-feng Hu, James Dawkins, Eduardo Marbán, Eugenio Cingolani
    Abstract:

    Background: Minimally-invasive TBX18 gene transfer creates physiologically-relevant Biological Pacemaker (BioP) activity for at least 2 weeks in pigs with complete heart block, providing evidence for therapeutic somatic reprogramming in a clinically-relevant disease model (Hu et al, Sci Trans Med 2014). It remains unknown how long Biological Pacemaker activity is maintained after TBX18 gene transfer. Hypothesis: We tested whether TBX18 gene transfer could create sustained BioP activity beyond two weeks. Methods: Adenoviral vectors expressing either TBX18 (n=3) or GFP (n=2) as a control were delivered into the high right ventricular septum via injection catheters (NOGA™ Myostar). Rate and rhythm were followed continuously for one month by implanted telemetry, and backup device utilization was quantified by serial Pacemaker interrogations. Physical activity was measured by a built-in accelerometer. Results: BioP activity was evident in TBX18 -transduced animals and persisted at least for 4 weeks. At week 4, maximal heart rate (HR,101±8 vs. 65±3bpm, p<0.05), daytime HR (79±4 vs. 53±1bpm, p<0.05), and electronic Pacemaker utilization (82±3 vs. 6±3%, p<0.05) were higher in TBX18 -transduced animals compared to GFP controls. Mean HR was borderline higher in TBX18 -transduced animals compared to GFP controls (HR=70±7 vs. 51±1bpm, p=0.11) as was night-time HR (70±5 vs. 51±0bpm, p=0.07). Mean daily activity tends to be greater in TBX18- transduced group (394±18 vs. 339±12 A.U, p=0.11). There were no significant differences of ventricular arrhythmia incidence between the two groups during 4 week follow-up. Cardiac enzymes, liver function, renal function, and systemic inflammatory markers remained unchanged in both groups during follow-up. Conclusions: TBX18 gene transfer can create stable BioP activity for at least 4 weeks, suggesting a potential long-term BioP effect after adenoviral gene transfer.

  • Biological Pacemaker created by minimally invasive somatic reprogramming in pigs with complete heart block
    Science Translational Medicine, 2014
    Co-Authors: Yu-feng Hu, James Dawkins, Eduardo Marbán, Eugenio Cingolani
    Abstract:

    Somatic reprogramming by reexpression of the embryonic transcription factor T-box 18 (TBX18) converts cardiomyocytes into Pacemaker cells. We hypothesized that this could be a viable therapeutic avenue for Pacemaker-dependent patients afflicted with device-related complications, and therefore tested whether adenoviral TBX18 gene transfer could create Biological Pacemaker activity in vivo in a large-animal model of complete heart block. Biological Pacemaker activity, originating from the intramyocardial injection site, was evident in TBX18-transduced animals starting at day 2 and persisted for the duration of the study (14 days) with minimal backup electronic Pacemaker use. Relative to controls transduced with a reporter gene, TBX18-transduced animals exhibited enhanced autonomic responses and physiologically superior chronotropic support of physical activity. Induced sinoatrial node cells could be identified by their distinctive morphology at the site of injection in TBX18-transduced animals, but not in controls. No local or systemic safety concerns arose. Thus, minimally invasive TBX18 gene transfer creates physiologically relevant Pacemaker activity in complete heart block, providing evidence for therapeutic somatic reprogramming in a clinically relevant disease model.

  • Biological Pacemaker created by percutaneous gene delivery via venous catheters in a porcine model of complete heart block
    Heart Rhythm, 2012
    Co-Authors: Eugenio Cingolani, Michael Shehata, Sumeet S Chugh, Eduardo Marbán
    Abstract:

    Background Pacemaker-dependent patients with device infection require temporary pacing while the infection is treated. External transthoracic pacing is painful and variably effective, while temporary pacing leads are susceptible to superinfection. Objective To create a Biological Pacemaker delivered via venous catheters in a porcine model of complete heart block, providing a temporary alternative/adjunct to external pacing devices without additional indwelling hardware. Methods Complete atrioventricular (AV) nodal block was induced in pigs by radiofrequency ablation after the implantation of a single-chamber electronic Pacemaker to maintain a ventricular backup rate of 50 beats/min. An adenoviral vector cocktail (K AAA + H2), expressing dominant-negative inward rectifier potassium channel (Kir2.1AAA) and hyperpolarization-activated cation channel (HCN2) genes, was injected into the AV junctional region via a NOGA Myostar catheter advanced through the femoral vein. Results Animals injected with K AAA + H2 maintained a physiologically relevant ventricular rate of 93.5 ± 7 beats/min (n = 4) compared with control animals (average rate, 59.4 ± 4 beats/min; n=6 at day 7 postinjection; P AAA + H2 group compared with the control ( P AAA + H2 (or its individual vectors) into the ventricular myocardium failed to elicit significant Pacemaker activity. Conclusions The right-sided delivery of K AAA + H2 to the AV junctional region provided physiologically relevant Biological pacing over a 14-day period. Our approach may provide temporary, bridge-to-device pacing for the effective clearance of infection prior to the reimplantation of a definitive electronic Pacemaker.

  • creation of a Biological Pacemaker by cell fusion
    Circulation Research, 2007
    Co-Authors: Yuji Kashiwakura, Eduardo Marbán
    Abstract:

    As an alternative to electronic Pacemakers, we explored the feasibility of converting ventricular myocytes into Pacemakers by somatic cell fusion. The idea is to create chemically induced fusion between myocytes and syngeneic fibroblasts engineered to express HCN1 Pacemaker channels (HCN1-fibroblasts). HCN1-fibroblasts were fused with freshly isolated guinea pig ventricular myocytes using polyethylene-glycol 1500. In vivo fused myocyte-HCN1-fibroblast cells exhibited spontaneously oscillating action potentials; the firing frequency increased with β-adrenergic stimulation. The heterokaryons created ectopic ventricular Pacemaker activity in vivo at the site of cell injection. Coculture of nonfused HCN1-fibroblasts and myocytes without polyethylene-glycol 1500 revealed no evidence of dye transfer, demonstrating that the I f -mediated Pacemaker activity arises from heterokaryons rather than electrotonic coupling. This nonviral, non-stem cell approach enables autologous, adult somatic cell therapy to create bioPacemakers.

Peter R. Brink - One of the best experts on this subject based on the ideXlab platform.

  • Physiological and Other Biological Pacemakers
    Electrical Diseases of the Heart, 2020
    Co-Authors: Michael R. Rosen, Ira S. Cohen, Peter R. Brink, Richard B Robinson
    Abstract:

    Physiological pacemaking in the heart is the province of the sinus node, in which a family of ionic currents contributes to the Pacemaker potential. Of paramount importance in initiating Pacemaker function is I f, an inward current carried by sodium through a family of channels that is hyperpolarization activated and cyclic nucleotide gated (HCN channels). In many settings where physiological pacemaking fails, therapy involves electronic pacing. Because of shortcomings in this otherwise excellent technology, there has been a search for Biological alternatives in which either gene or cell therapy is used to decrease outward current or increase inward current to provide Pacemaker function. The various technologies used will be summarized as well as directions for optimizing Biological Pacemaker function and for using them in tandem with electronic units.

  • 0406 keratinocyte derived cardiomyocytes provide in vivo Biological Pacemaker function
    Archives of Cardiovascular Diseases Supplements, 2016
    Co-Authors: Samuel Chauveau, Irina A Potapova, Peter Danilo, Yevgeniy Anyukhovskiy, Meital Benari, Shelly Naor, Tania Rahim, Stephanie Burke, Yaping Jiang, Peter R. Brink
    Abstract:

    Objective We investigated Pacemaker function of iPSC-CM in a canine complete heart block model. Methods Embryoid bodies (EBs) were derived from human keratinocytes and their gene expression profile and markers of differentiation were identified. We recorded their action potential characteristics, including phase 4 depolarization, automaticity, response to ivabradine, and Pacemaker current, If, as well. Atrio-ventricular blocked dogs were immunosuppressed and instrumented with a VVI Pacemaker. Forty-75 rhythmically contracting EBs (totaling 1.3-2x106 cells) were injected subepicardially into the anterobasal left ventricle. ECGs and 24-h Holter recordings were made biweekly. After 4- 13 weeks, epinephrine (EPI) (1 μg/Kg/min) was infused and the heart removed for histological or electrophysiological study. Results IPSC-CMs largely lost their markers of pluripotency and were positive for cardiac-specific markers instead. Automaticity of IPSC-CMs was identified and confirmed to be If-dependent. Epicardial pacing of the injection site identified matching beats arising from that site by the end of week 1 of implantation. By week 4, 20% of beats were electronically paced and 60-80% of beats were matching. Maximum night and day rates of matching beats were 53±6.9 and 68±10.4 bpm respectively at 4 weeks. EPI increased rate of matching beats from 35±4.3 to 65±4.0 bpm. Incubation of EBs with the vital dye, Dil, revealed the persistence of injected cells at the site of administration. Conclusions IPSC-CM can integrate into host myocardium and create a Biological Pacemaker. While this is a promising development, rate and rhythm of the iPSC-CM Pacemakers remain to be optimized. The author hereby declares no conflict of interest

  • Stem cell-based Biological Pacemakers from proof of principle to therapy: a review.
    Cytotherapy, 2014
    Co-Authors: Samuel Chauveau, Peter R. Brink, Ira S. Cohen
    Abstract:

    Abstract Electronic Pacemakers are the standard therapy for bradycardia-related symptoms but have shortcomings. Over the past 15 years, experimental evidence has demonstrated that gene and cell-based therapies can create a Biological Pacemaker. Recently, physiologically acceptable rates have been reported with an adenovirus-based approach. However, adenovirus-based protein expression does not last more than 4 weeks, which limits its clinical applicability. Cell-based platforms are potential candidates for longer expression. Currently there are two cell-based approaches being tested: (i) mesenchymal stem cells used as a suitcase for delivering Pacemaker genes and (ii) pluripotent stem cells differentiated down a cardiac lineage with endogenous Pacemaker activity. This review examines the current achievements in engineering a Biological Pacemaker, defines the patient population for whom this device would be useful and identifies the challenges still ahead before cell therapy can replace current electronic devices.

  • The road to Biological pacing
    Nature Reviews Cardiology, 2011
    Co-Authors: Michael R. Rosen, Richard B Robinson, Peter R. Brink, Ira S. Cohen
    Abstract:

    The field of Biological pacing is entering its second decade of active investigation. The inception of this area of study was serendipitous, deriving largely from observations made by several teams of investigators, whose common interest was to understand the mechanisms governing cardiac impulse initiation. Research directions taken have fallen under the broad headings of gene therapy and cell therapy, and biomaterials research has also begun to enter the field. In this Review, we revisit certain milestones achieved through the construction of a 'roadmap' in Biological pacing. Whether the end result will be a clinically applicable Biological Pacemaker is still uncertain. However, promising constructs that achieve physiologically relevant heart rates and good autonomic responsiveness are now available, and proof of principle studies are giving way to translation to large-animal models in long-term studies. Provided that interest in the field continues, the next decade should see either Biological Pacemakers become a clinical reality or the improvement of electronic Pacemakers to a point where the Biological approach is no longer a viable alternative. Biological pacing is a disruptive technology that aims first to improve upon, then to supplement and, eventually, to replace electronic pacing Biological pacing utilizes the tools of gene and cell therapy to introduce Pacemaker function to preselected regions of the heart Gene therapy focuses on delivery via viral vectors; whereas cell therapy uses either mesenchymal stem cells as delivery systems or cells with sinoatrial node-like properties derived from pluripotent stem cells Proof-of-concept has been achieved in studies of large animals in complete heart block and, in some instances, sinoatrial node dysfunction Substantial barriers remain to be overcome before clinical trials of Biological pacing can be begun, but the field is advancing steadily towards this goal The field of Biological cardiac pacing, which aims to improve upon, supplement and, eventually, to replace electronic pacing has come a long way since its inception more than a decade ago. Broadly, research has been focused on gene and cell therapy. In this Review, Rosen and colleagues highlight milestones achieved through the construction of a 'roadmap' in Biological pacing, and discuss the barriers that remain to be overcome before clinical trials of Biological pacing can be begun.

  • xenografted adult human mesenchymal stem cells provide a platform for sustained Biological Pacemaker function in canine heart
    Circulation, 2007
    Co-Authors: Alexander N. Plotnikov, Irina A Potapova, Zhongju Lu, Iryna N Shlapakova, Peter Danilo, Matthias Szabolcs, Beverly H Lorell, Amy B Rosen, R T Mathias, Peter R. Brink
    Abstract:

    Background— Biological pacemaking has been performed with viral vectors, human embryonic stem cells, and adult human mesenchymal stem cells (hMSCs) as delivery systems. Only with human embryonic stem cells are data available regarding stability for >2 to 3 weeks, and here, immunosuppression has been used to facilitate survival of xenografts. The purpose of the present study was to determine whether hMSCs provide stable impulse initiation over 6 weeks without the use of immunosuppression, the “dose” of hMSCs that ensures function over this period, and the catecholamine responsiveness of hMSC-packaged Pacemakers. Methods and Results— A full-length mHCN2 cDNA subcloned in a pIRES2-EGFP vector was electroporated into hMSCs. Transfection efficiency was estimated by GFP expression. IHCN2 was measured with patch clamp, and cells were administered into the left ventricular anterior wall of adult dogs in complete heart block and with backup electronic Pacemakers. Studies encompassed 6 weeks. IHCN2 for all cells wa...