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Biological Pacemaker

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Richard B Robinson – 1st expert on this subject based on the ideXlab platform

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

Stephanie Protze – 2nd expert on this subject based on the ideXlab platform

  • sinoatrial node cardiomyocytes derived from human pluripotent cells function as a Biological Pacemaker
    Nature Biotechnology, 2017
    Co-Authors: Stephanie Protze, Gordon Keller, Udi Nussinovitch, Lily Ohana, Peter H Backx, Lior Gepstein

    Abstract:

    Cardiomyocytes derived from human stem cells act as a Biological Pacemaker in the rat heart.

  • Sinoatrial node cardiomyocytes derived from human pluripotent cells function as a Biological Pacemaker
    Nature Biotechnology, 2017
    Co-Authors: Stephanie Protze, Udi Nussinovitch, Lily Ohana, Peter H Backx, Lior Gepstein, Gordon M Keller

    Abstract:

    Cardiomyocytes derived from human stem cells act as a Biological Pacemaker in the rat heart. The sinoatrial node (SAN) is the primary Pacemaker of the heart and controls heart rate throughout life. Failure of SAN function due to congenital disease or aging results in slowing of the heart rate and inefficient blood circulation, a condition treated by implantation of an electronic Pacemaker. The ability to produce Pacemaker cells in vitro could lead to an alternative, Biological Pacemaker therapy in which the failing SAN is replaced through cell transplantation. Here we describe a transgene-independent method for the generation of SAN-like Pacemaker cells (SANLPCs) from human pluripotent stem cells by stage-specific manipulation of developmental signaling pathways. SANLPCs are identified as NKX2-5^− cardiomyocytes that express markers of the SAN lineage and display typical Pacemaker action potentials, ion current profiles and chronotropic responses. When transplanted into the apex of rat hearts, SANLPCs are able to pace the host tissue, demonstrating their capacity to function as a Biological Pacemaker.

Gordon Keller – 3rd expert on this subject based on the ideXlab platform

  • sinoatrial node cardiomyocytes derived from human pluripotent cells function as a Biological Pacemaker
    Nature Biotechnology, 2017
    Co-Authors: Stephanie Protze, Gordon Keller, Udi Nussinovitch, Lily Ohana, Peter H Backx, Lior Gepstein

    Abstract:

    Cardiomyocytes derived from human stem cells act as a Biological Pacemaker in the rat heart.