Editors
Igor�R.�Efimov, Fu�Siong�Ng and Jacob�I.�Laughner

Cardiac Bioelectric Therapy

Mechanisms and Practical Implications

2nd ed. 2021
Editors
Igor�R.�Efimov
Department of Biomedical Engineering, The George Washington University, Washington, DC, USA
Fu�Siong�Ng
National Heart & Lung Institute, Imperial College London, London, UK
Jacob�I.�Laughner
Philips EPD Solutions, Cambridge, MA, USA
ISBN 978-3-030-63354-7e-ISBN 978-3-030-63355-4
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Foreword

It is a rare privilege to contribute a foreword to the second edition of this remarkable book by Drs. Igor Efimov, Fu Siong Ng, and Jacob Laughner. Cardiac electrophysiology is a magical field that connects the most fundamental basic science to the fascinating technologies to study electrical phenomena in the heart and most of all to treat patients with heart disease. Cardiac disease is responsible for 34 deaths per minute in the world today (17�million deaths/year), and by some estimates, a staggering 12�million deaths (22 deaths/minute) are related to sudden cardiac death (due to serious ventricular arrhythmias). This is the challenge faced by scientists and clinicians focused on the study of cardiac bioelectrical phenomena and their modulation. The second edition of this book has been eagerly awaited and lives up to its promise, beautifully building on the first edition. The readers of this remarkable book will be enthralled to read about the history of how pioneers studied the electrical phenomena of the heart and how this work has helped inform therapeutics. Almost every therapy we offer to patients in 2020 for cardiac care involves bioelectronics (from diagnosis using ECGs to therapy with catheter ablation and implanted electronic device); indeed the highest level of evidence for preventing sudden deaths is the implanted defibrillator. The continued importance and success of the field is evidenced by the remarkable explosion of technologies for scientific investigation, which have also opened up powerful bioelectronic therapeutic approaches to heart disease and arrhythmias. Specific new areas such as microelectronics and advanced computing in devices are highlighted in this edition. Professor Efimov, a pioneer and scholar of the field, and his esteemed colleagues have been able to collate a treasure and I am certain that the book will continue to inspire the readers, some of whom are surely contemplating an area of specialization, and it is hoped they will choose this field and help our patients!

Kalyanam�Shivkumar
September 2020
Preface

Cardiovascular science and technology provided the foundation for an unprecedented increase in life expectancy, which was sustained for nearly half a century, starting from 1970. The primary cause of lifespan increase by a decade is improved diagnostics and therapy of heart disease leading to the declining cardiovascular mortality. Cardiac bioelectric therapy was among the major contributors to the reduction of cardiovascular mortality. Classical examples of such lifesaving technologies are cardiac pacemaker, implantable cardioverter defibrillators, and ablation of arrhythmias. However, regrettably, there is now an evidence of the reversal of this trend during the last decade, which necessitated doubling our efforts in developing a new generation of the diagnostic and therapeutic approaches to treat heart disease.

Reductionist Approach to Arrhythmia

A dramatic increase in understanding of the molecular mechanisms of normal and pathological cellular electrophysiology led to the development of new theories of arrhythmia. A number of these theories have been supported by a convincing empirical evidence ?from cell to bedside.? And, as a result, the field has been driven by promises of elegant ?silver bullet? pharmacological solutions to treat lethal cardiac arrhythmias. Nearly every generation of electrophysiologists has come up with a target for their own silver bullet: sodium channel, calcium channel, potassium channel, gap junction, and so forth. Visions of several generations of electrophysiologists have crystallized into a theory of channelopathies.

There is a proverb: nearly every new thought is a long forgotten one. The state of arrhythmia research is reminiscent in some sense to an earlier history of the elementary particle physics. It appeared to most physicists at the time that the foundation of laws of matter can be eloquently explained by interactions of few elementary particles and a handful of fundamental laws governing these interactions. Yet, as more and more new particles and/or novel peculiar properties of the existing particles were uncovered, the increasingly more sophisticated theories were produced, making the elegance and eloquence of the earlier theories irrelevant.

Cardiac electrophysiology went along a very similar path in search of arrhythmia therapy. A giant of the field, Carl J. Wiggers, drafted a roadmap in 1940: ?As to the fundamental mechanisms of fibrillation we have plenty of theories, but none is universally accepted ? they all center around two ideas, viz. (a) that the impulses arise from centers, or pacemakers, or (b) that the condition is caused by the re-entry of impulses and the formation of circles of excitation.?1

The old ion-channel-based theory seemed to have done a pretty good job explaining both focal and reentrant theories of arrhythmia. These early theories of arrhythmia, with their four classes of antiarrhythmic drugs, were almost Aristotelian. But they fell under the pressure of the empirical evidence:2 ever multiplying channel isoforms and subunits, alternative splicing variants, mutations in genes encoding ion channels and related proteins, the involvement of numerous increasingly complex signaling pathways, epigenetic regulation of transcription, cell memory, circadian variability, gene-gene interaction, and chromatin landscape. These important players had been unknown in the past and will present new opportunities in the future, if gene editing, epigenetic control, and novel approaches will become a clinical reality one day.

Can a cardiac arrhythmia with broad clinical impact be explained within a framework based on a single channel biophysics, or a signaling pathway, or even a single cell mechanism? And, most importantly, can a therapy be developed for arrhythmia based on such a mechanism? Despite the explosion in the numbers of filed patents aimed at offering such answers, it is becoming more and more apparent that these questions will not be so easy to answer within the reductionist paradigm. Integrative approaches are needed to synthesize the wealth of knowledge accumulated by a century of the reductionist science.

Integrative Approach

Integrative physiologists looked at the problem of arrhythmia from an entirely different angle: How can we restore normal heart rhythm when sinoatrial or atrioventricular nodes fail with the technology at hand? How can one terminate lethal ventricular fibrillation using cardiovascular engineering approaches, when the pharmacological approach failed? Electrotherapy, both device and ablation, has emerged as the only effective therapy to treat arrhythmia, often without precise knowledge of the mechanisms of arrhythmia it treats. History of cardiac bioelectric therapy is a long and fascinating one, spanning several centuries and many countries. Ideas of using electricity for treating cardiac disorders have been born in the minds of the Italian, French, and British physiologists and physicians as evident from the numerous eighteenth-century publications in these languages. The nineteenth-century cardiac physiology framed recognition of arrhythmia as a direct cause of death and provided a compelling evidence for the ability of electric stimulation to restore normal rhythm. The twentieth-century cardiovascular physiology finally brought to fruition three centuries of research and developed an array of bioelectric therapies that save lives of millions of patients worldwide.

But the twenty-first century has a truly transformative beginning in the field of cardiac bioelectric therapy. Novel implantable and wearable devices are becoming truly widespread among hundreds of millions of patients and healthy individuals, who are concerned with their cardiovascular health and take a proactive approach. Machine learning is an excellent example of an emerging breakthrough approach to decipher electrophysiological information collected by myriads of sensors, which are becoming more and more ubiquitous. An advent of organ conformal flexible and stretchable bioelectronics will usher in a new era of integration of cybernetics with our biology, powered by rapidly evolving machine learning and artificial intelligence. These advances create conditions for population-wide surveillance of cardiovascular health becoming a reality. However, it also opens a Pandora box of safety concerns due to security vulnerability of digital technologies.

And finally, we are about to enter an era of synthesis of integrative and reductionist approaches. A growing wealth of information from OMICS technologies is merging with functional high-fidelity multidimensional physiological data.

Igor�R.�Efimov
Fu�Siong�Ng
Jacob�I.�Laughner
Washington, DC, USALondon, UKCambridge, MA, USA
Contents
Part I?History of Electrotherapy
Srijoy�Mahapatra
Hana�Akselrod, Mark�W.�Kroll and Michael�V.�Orlov
Ivan�Cakulev, Andrew�L.�Wit and Albert�L.�Waldo
Sharon�A.�George
Part II?Theory of Electric Stimulation and Defibrillation
Deborah�L.�Janks and Bradley�J.�Roth
Natalia�Trayanova and Gernot�Plank
Part III?Electrode Mapping and Defibrillation
Richard�B.�Schuessler
Derek�J.�Dosdall and Raymond�E.�Ideker
Matthias�Lange and Derek�J.�Dosdall
Part IV?Optical Mapping of Stimulation and Defibrillation
Andre�G.�Kleber and Anne�M.�Gillis
Bradley�J.�Roth, Veniamin�Y.�Sidorov and John�P.�Wikswo
Crystal�M.�Ripplinger and Igor�R.�Efimov
Olivier�Bernus and Richard�D.�Walton
Part V?Methodology
Zexu�Lin and Sharon�A.�George
Vladimir�P.�Nikolski and Igor�R.�Efimov
Jeff�Gillberg, Troy�Jackson and Paul�Ziegler
Matthew�S.�Sulkin and Jason�Meyers
Part VI?Novel and Future Cardiac Electrotherapies
Balvinder�S.�Handa and Fu�Siong�Ng
Paul�R.�Roberts
Parikshit�S.�Sharma and Pugazhendhi�Vijayaraman
Wan-Tai�M.�Au-Yeung, Rahul�Kumar�Sevakula, Jagmeet�P.�Singh, E.�Kevin�Heist, Eric�M.�Isselbacher and Antonis�A.�Armoundas
Antonis�A.�Armoundas, Jagmeet�P.�Singh, E.�Kevin�Heist and Eric�M.�Isselbacher
Bal�zs��rd�g, Antoine�A.�F.�de�Vries and Dani�l�A.�Pijnappels
Kedar�Aras, John�A.�Rogers and Igor�R.�Efimov
Charles�D.�Swerdlow and Michael�R.�Gold
David�Slotwiner, Arnab�Ray, Kevin�Fu and Bruce�L.�Wilkoff
Index 425
Contributors
Hana�AkselrodMS
Freelance Writer, Boston, MA, USA
Kedar�ArasPhD
Department of Biomedical Engineering, Cardiovascular Engineering Laboratory, The George Washington University, Washington, DC, USA
Antonis�A.�ArmoundasPhD
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
Institute for Medical Engineering and Science, Massachusetts Institute of Technology, Cambridge, MA, USA
Wan-Tai�M.�Au-YeungPhD
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
Omer�BerenfeldPhD
Center for Arrhythmia Research, University of Michigan, Ann Arbor, MI, USA
Olivier�BernusPhD
Universit� de Bordeaux, Electrophysiology and Heart Modeling Institute Liryc, CRCTB U1045, Avenue du Haut-L�v�que�? Xavier Arnozan, Pessac, France
Ivan�CakulevMD
Case Western Reserve University School of Medicine, University Hospitals of Cleveland, Cleveland, OH, USA
David�CalvoMD, PhD
Arrhythmia Unit, Cardiology Department, Hospital Universitario Central de Asturias, Instituto de Investigaci�n Sanitaria del Principado de Asturias, Oviedo, Spain
Derek�J.�DosdallPhD
Division of Cardiothoracic Surgery, Department of Surgery and The Nora Eccles Harrison Cardiovascular Research Training Institute, University of Utah, Salt Lake City, UT, USA
Igor�R.�EfimovPhD
Department of Biomedical Engineering, The George Washington University, Washington, DC, USA
Kevin�FuPhD
University of Michigan, Ann Arbor, MI, USA
Sharon�A.�GeorgePhD
Department of Biomedical Engineering, Science and Engineering Hall, The George Washington University, Washington, DC, USA
Jeff�GillbergMS
Medtronic plc., Mounds View, MN, USA
Anne�M.�GillisMD, FRCPC
Department of Cardiac Sciences, University of Calgary, Libin Cardiovascular Institute, Calgary, AB, Canada
Michael�R.�GoldMD, PhD
Division of Cardiology, Medical University of South Carolina, Charleston, SC, USA
Balvinder�S.�HandaBSc, MRCP
National Heart & Lung Institute, Imperial College London, London, UK
E.�Kevin�HeistMD, PhD
The Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA
Craig�S.�HenriquezPhD
Department of Biomedical Engineering, Duke University, Durham, NC, USA
Raymond�E.�IdekerMD, PhD
Division of Cardiovascular Disease, University of Alabama at Birmingham, Birmingham, AL, USA
Eric�M.�IsselbacherMD, MSc
Healthcare Transformation Lab, Massachusetts General Hospital, Boston, MA, USA
Troy�JacksonMS
Medtronic plc., Mounds View, MN, USA
Deborah�L.�JanksPhD
Department of Physics, Oakland University, Rochester, MI, USA
Andre�G.�KleberMD
Department of Pathology, Harvard Medical School, Boston, MA, USA
Mark�W.�KrollPhD, FACC, FHRS, FIEEE, FAIMBE
Mark Kroll & Associates, LLC, Crystal Bay, MN, USA
University of Minnesota, Minneapolis, MN, USA
Matthias�LangePhD
The Nora Eccles Harrison Cardiovascular Research Training Institute, University of Utah, Salt Lake City, UT, USA
Zexu�LinMS
The George Washington University, Washington, DC, USA
Srijoy�MahapatraMD, MBA
University of Minnesota/Fairview, Minneapolis, MN, USA
Jason�MeyersMD, PHD
Iowa Heart Center, Des Moines, IA, USA
Fu�Siong�NgMRCP, PhD
National Heart & Lung Institute, Imperial College London, London, UK
Vladimir�P.�NikolskiPhD
Cardiac Rhythm and Heart Failure Department, Medtronic, Mounds View, MN, USA
Bal�zs��rd�gPhD
Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
Michael�V.�OrlovMD, PhD
Steward St. Elizabeth?s Medical Center of Boston, Tufts University School of Medicine, Boston, MA, USA
Dani�l�A.�PijnappelsPhD
Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
Gernot�PlankPhD
Gottfried Schatz Research Center (for Cell Signaling, Metabolism and Aging), Division of Biophysics, Graz, Austria
Arnab�RayPhD
Abbott, Sylmar, CA, USA
Crystal�M.�RipplingerPhD, FHRS, FAHA
University of California at Davis, Department of Pharmacology, UC Davis School of Medicine, Davis, CA, USA
Paul�R.�RobertsMD FRCP
University Hospital Southampton NHS Foundation Trust, Southampton, UK
John�A.�RogersPhD
Northwestern University, Evanston, IL, USA
Bradley�J.�RothPh.D.
Department of Physics, Oakland University, Rochester, MI, USA
Richard�B.�SchuesslerPhD
Cardiothoracic Surgery Research Laboratory, Division of Cardiothoracic Surgery, Department of Surgery, Washington University School of Medicine, St. Louis, MO, USA
Rahul�Kumar�SevakulaPhD
Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA
Parikshit�S.�SharmaMD
Division of Cardiology, Rush University Medical Center, Chicago, IL, USA
Veniamin�Y.�SidorovPhD
Department of Biomedical Engineering, The Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, Nashville, TN, USA
Jagmeet�P.�SinghMD, PhD
The Cardiac Arrhythmia Service, Massachusetts General Hospital, Boston, MA, USA
David�SlotwinerMD
Weill Cornell Medical College, New York, NY, USA
Matthew�S.�SulkinPHD
Boston Scientific, Electrophysiology, Arden Hills, MN, USA
Charles�D.�SwerdlowMD
Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
Natalia�TrayanovaPhD
Department of Biomedical Engineering and Institute for Computational Medicine, Alliance for Cardiovascular Diagnostic and Treatment Innovation (ADVANCE), Johns Hopkins University, Baltimore, MD, USA
Leslie�TungPhD
Department of Biomedical Engineering, The Johns Hopkins University, School of Medicine, Baltimore, MD, USA
Pugazhendhi�VijayaramanMD
Geisinger Commonwealth School of Medicine, Geisinger Heart Institute, Wilkes-Barre, PA, USA
Antoine�A.�F.�de�VriesPhD
Laboratory of Experimental Cardiology, Department of Cardiology, Leiden University Medical Center, Leiden, The Netherlands
Albert�L.�WaldoMD, PhD (Hon)
Case Western Reserve University, Harrington Heart & Vascular Institute, University Hospitals Cleveland Medical Center, Division of Cardiovascular Medicine, Cleveland, OH, USA
Richard�D.�WaltonPhD
Universit� de Bordeaux, Electrophysiology and Heart Modeling Institute Liryc, CRCTB U1045, Avenue du Haut-L�v�que�? Xavier Arnozan, Pessac, France
John�P.�WikswoPh.D.
Departments of Biomedical Engineering, Molecular Physiology and Biophysics, and Physics and Astronomy, The Vanderbilt Institute for Integrative Biosystems Research and Education, Vanderbilt University, Nashville, TN, USA
Bruce�L.�WilkoffMD
Cleveland Clinic, Cleveland, OH, USA
Andrew�L.�WitPhD, FACC
Department of Pharmacology, College of Physicians and Surgeons of Columbia University, New York City, NY, USA
Wenjun�YingPhD
Institute of Natural Sciences and School of Mathematical Sciences, Shanghai Jiao Tong University, Shanghai, China
Paul�ZieglerMS
Medtronic plc., Mounds View, MN, USA