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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 (17million deaths/year), and by some estimates, a staggering 12million 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!
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.
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 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.