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PERSPECTIVE article

Front. Physiol., 15 July 2020 | https://doi.org/10.3389/fphys.2020.00854

The Future of Physiology: Cardiac Electrophysiology

  • Department of Experimental Cardiology, Academic Medical Center, Amsterdam, Netherlands

Is cardiac electrophysiology complete? What are the challenges that are to be met in cardiac electrophysiology and how can we best engage these? These questions will be addressed in view of the progressing subspecialization of the field. A suggested answer lies in multidisciplinary and extradisciplinary approaches.

Introduction

Burdon Sanderson and Page wrote in 1879: “…we owe most to the labours of Engelmann, whose researches … on the electromotive properties of the resting heart, and on the electrical changes which immediately follow excitation, leave little more to be done” (Burdon-Sanderson and Page, 1879). They suggested that almost every question on cardiac electrophysiology had been answered and that the subject had been covered by their predecessor Engelmann (1877). Cardiac electrophysiology was complete. However, almost 120 years later the question whether cardiac electrophysiology was complete was addressed again by de Bakker in his inaugural lecture (de Bakker, 1999). de Bakker (1999) pointed to the many recent and new developments in the field and answered the question in the negative. There were still many challenges ahead in cardiac electrophysiology.

Indeed, after the publications of Burdon Sanderson and Page cardiac electrophysiology has flourished:

– Reentry was described as a potential mechanism underlying clinical arrhythmias (Mines, 1914).

– The Long QT syndromes were recognized as an entity (Jervell and Lange-Nielsen, 1957).

– The role of the autonomic nervous system on cardiac electrophysiology was studied (Schwartz et al., 1977; Shivkumar et al., 2016).

– The transmembrane current underlying pacemaking was discovered (DiFrancesco and Ohba, 1978).

– Ischemia-induced arrhythmias were mechanistically understood (Janse et al., 1980).

– Electrical cardioversion was successfully applied to stop lethal arrhythmias (Lown et al., 1986).

– The intricate relation between anatomy and function of the sinus and atrioventricular nodes was understood (Opthof, 1988; McGuire et al., 1996).

– The histology of myocardial infarction was linked to post-MI VTs (de Bakker et al., 1993).

– The coupling between cardiac mechanics and cardiac electrophysiology has been described (Franz, 1996; Kohl et al., 1998).

– The pulmonary vein myocardium was found as the origin of AF (Haissaguerre et al., 1998).

– The relation between embryological development and arrhythmias was established (Boukens and Christoffels, 2012).

Many more important and life-changing accomplishments of cardiac electrophysiology can be described here. As a spin-off of these insights, pharmacological and device therapies have been designed and new, -molecular biological- therapies are under development. The number of new inventions and breakthroughs have been almost endless and unanswered questions in cardiac electrophysiology remain. A few of these questions are enumerated in the table, some clinically relevant, others with a more basic science origin. The list is not intended to be complete or in order of relevance. Therefore, cardiac electrophysiology appears to have a future. However, is the subspecialization fit to address these questions?

The Development of Cardiac Electrophysiology as a Subspecialization

Cardiac electrophysiology has a rich history (Lüderitz, 2002) and it is not easy to determine when cardiac electrophysiology constituted a distinct subspecialty of physiology and who was the first cardiac electrophysiologist. Burdon-Sanderson with his work on the cardiac currents resulting from local “injury” probably qualifies as the first cardiac electrophysiologist because he described what we now name a monophasic action potential or MAP (Burdon-Sanderson and Page, 1879; Franz, 1983). His pupil, Waller subsequently recorded the first electrocardiogram in man in 1887 (Waller, 1887). Thus, Burdon Sanderson and Waller shared and transferred their common interest in cardiac electrophysiology and thereby constituted the subspecialty. Nevertheless, the interest of these researchers was much wider than cardiac electrophysiology alone. They also studied the electrophysiology of nerves and plants (the fly trap), the effects of anesthesia and the influence of drugs on muscle contraction, to name but a few topics of their studies (Waller, 1887, 1910).

In the course of time, physiology have undergone further (sub)specialization. Physiology has developed into electrophysiology and cardiac electrophysiology (Weidmann, 1951). This course of (sub)specialization has followed the reductionist approach in science in general. In this approach the researcher uses progressively smaller and simpler models to exclude as many as possible confounding factors and to control all factors excepting the one that he/she is interested in. Indeed, at the same time cardiac electrophysiology evolved from the study of organisms (Waller, 1887) to that of organs (Mines, 1913) multicellular preparations (Kléber and Riegger, 1987) cells, expression systems, subcellular domains (Sanchez-Alonso et al., 2016; Rivaud et al., 2020), genes (Remme et al., 2006), or computer models (Shaw and Rudy, 1997; Hoogendijk et al., 2011). The reductionist development of scientific fields has also transpired in cardiac electrophysiology from which now a branch of cardiac cellular electrophysiology exists with dedicated textbooks and a European Working Group of Cardiac Cellular Electrophysiology (EWGCCE) that is part of the European Society of Cardiology. The identification of subcellular microdomains heralds the further subspecialization of the field in cardiac subcellular electrophysiology.

The website of Frontiers in Physiology1 is an example of the pedigree of physiology. It mentions 28 subspecialty sections amongst which are Autonomic Neuroscience, Biophysics, Cardiac Electrophysiology, Chronobiology, Clinical and Translational Physiology, Computational Physiology and Medicine, Embryonic and Developmental Physiology, Exercise Physiology, Integrative Physiology, Lipid and Fatty Acid Research, Medical Physics and Imaging, Membrane Physiology, and Membrane Biophysics. These subspecialties are not mutually exclusive. For example, studies on the Brugada Syndrome, a potentially lethal cardiac arrhythmia syndrome occurring at a relatively young age, are related to all of the above enumerated subspecialties of Frontiers in Physiology, but also to Frontiers in Cardiovascular Medicine (subspecialty Cardiac Rhythmology) (Antzelevitch et al., 2005; Hoogendijk et al., 2010; Zhang et al., 2015).

Although the reductionist approach is a powerful tool to identify mechanisms it has potential drawbacks. The results of reductionist studies cannot always be translated to more integrative levels of application. An example in cardiac electrophysiology is the use of the mouse as a model for human electrophysiology. Although the mouse is a good model for many mammalian characteristics including genetics, its ventricular action potential differs from that of man. Genetic studies on ventricular electrophysiology in mice therefore should be translated with caution to human electrophysiology (London, 2001). Another example is that of the use of a small portion of the ventricular wall as a model for the intact heart (Opthof et al., 2007).

The branching process (in progressively more subspecialities) facilitates but may also hinder engagement of the unmet challenges in cardiac electrophysiology. It is clear that within the domains of knowledge and techniques pertaining to cardiac electrophysiology we are more likely capable of finding an answer to the question “How does the Purkinje network relate to arrhythmias?” than to the question “How do we build a (human) heart?” (Table 1). Thus, it appears that physiology has branched into too many sub- and infra-specializations to allow a more generalist ‘integrative’ approach. How can we best address the unanswered questions?

TABLE 1
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Table 1. Some questions!

Integrative Research

In view of the immense growth of published knowledge in the course of the 20th century (Coronel, 2020) it would appear to be impossible to combine this knowledge in one person and to become a generalist again. Therefore, we need to resort to collaboration with other scientists to complement the missing knowledge. Multidisciplinary research, the collaborative effort of scientists of various specializations and disciplines to solve a common problem, has been very successful.

Purkynje was the founder of the modern physiological laboratory and already was aware of the power of combining multiple disciplines (Travnickova, 1987). Multidisciplinarity was also applied by Dirk Durrer who combined the disciplines medicine, biology, biochemistry, electronics and physics (and a well-equipped workshop) for his research on cardiac electrophysiology and arrhythmias (Durrer et al., 1970). Many electrophysiological labs have followed this example and now also incorporate molecular biology, genetics, imaging, artificial intelligence, and developmental biology (stem cell biology) as disciplines to support electrophysiological research. The added value of the collaborations stems from the novel insights and techniques obtained in each discipline or from the discovery of new (genetic) syndromes (Early repolarization syndrome and Brugada syndrome). These insights/techniques encompass -amongst others- new model systems (for example, pluripotent stem cells), enlarged computing power, and new imaging modalities (scanning ion conductance microscopy, near infrared optical mapping in explanted human hearts) (Hansen et al., 2018). It remains a challenge to select the best possible fitting (animal) model to address a research also in more integrative modes of research. The best model for human (electrophysiology) remains the human, although this often is not ethically appropriate.

Multidisciplinary research potentially has an impact that reaches far outside the field of cardiac electrophysiology. In most examples of multidisciplinary research, the central research question or hypothesis is generated from a co-ordinating specialization to which the contributors from the other disciplines apply their knowledge. The question ‘How do we diagnose and manage congenital arrhythmia syndromes?’ can be solved by asking geneticists and molecular biologists to join a team of cardiologists.

Extradisciplinary research constitutes a particular mode of multidisciplinary research. This describes the scientific study of a research question or hypothesis generated in a different discipline (or subspecialty). Extradisciplinary research is a way to overcome the drawbacks of a too far progressed specialization and a way to a more integrative research approach of physiology. When cardiac electrophysiology was in its early days, the various disciplines were combined in a single person and extradisciplinary research was performed as a matter of course. A problem in plant physiology could thus be solved by applying knowledge from the mammalian heart and vice versa. Extradisciplinary input to cardiac electrophysiology can be anticipated from mathematics (inverse electrocardiography), developmental biology (congenital arrhythmia syndromes), and neurology (arrhythmia mechanisms). On the other hand, cardiac electrophysiology may impact on heart failure management (pacing), and cardiac repair by biological tissue constructs.

Cardiac arrhythmias are often associated with cardiac and extracardiac morbidities like obesity, hypertension, diabetes, atherosclerosis and neurological disorders. The exact contribution of these co-morbidities to cardiac arrhythmogenesis is often not known. A solution to these question lies in unraveling the interaction between extracardiac factors and cardiac electrophysiology by asking endocrinologists, immunologists and neurologists to address cardiac arrhythmogenesis and by stimulating cardiac electrophysiologists to perform extracardiac studies in extradisciplinary approaches.

Thus, if we wish to advance cardiac electrophysiology into the future, we need to allow a ‘generalist’ view on the subject by invoking other disciplines to operate on our turf. On the other hand, cardiac electrophysiology may well be fit to address questions on other fields of research.

Conclusion

Although cardiac electrophysiology has a rich history it is far from complete. There are still many questions that need to be resolved. However, cardiac electrophysiology has seen the emergence of subspecialties that may hinder a more generalist tackling of research. A plea is made for a multidisciplinary research and for extradisciplinary research in particular. As with all collaborative projects, the success of extradisciplinary research depends on mutual trust and clear communication between the scientists of the various disciplines.

Author Contributions

The author confirms being the sole contributor of this work and has approved it for publication.

Conflict of Interest

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Footnotes

  1. ^ www.frontiersin.org

References

Antzelevitch, C., Brugada, P., Borggrefe, M., Brugada, J., Brugada, R., Corrado, D., et al. (2005). Brugada syndrome: report of the second consensus conference: endorsed by the heart rhythm society and the european heart rhythm association. Circulation 111, 659–670. doi: 10.1161/01.cir.0000152479.54298.51

CrossRef Full Text | Google Scholar

Boukens, B. J., and Christoffels, V. M. (2012). Electrophysiological patterning of the heart. Pediatr. Cardiol. 33, 900–906. doi: 10.1007/s00246-012-0237-4

PubMed Abstract | CrossRef Full Text | Google Scholar

Burdon-Sanderson, J., and Page, F. J. M. (1879). On the time relations of the excitatory process in the ventricle of the heart of the frog. J. Physiol. 2, 384–428.

Google Scholar

Coronel, R. (2020). Confirmative, consensual, competitive and controversial puiblication strategies for a career in physiology. Front. Physiol. 10, 1–2.

Google Scholar

de Bakker, J. M. (1999). Over Hoofdwegen En Sluipwegen. Utrecht: Utrecht University.

Google Scholar

de Bakker, J. M., van Capelle, F. J., Janse, M. J., Tasseron, S., Vermeulen, J. T., de Jonge, N., et al. (1993). Slow conduction in the infarcted human heart. ‘Zigzag’ course of activation. Circulation 88, 915–926. doi: 10.1161/01.cir.88.3.915

CrossRef Full Text | Google Scholar

DiFrancesco, D., and Ohba, M. (1978). Dependence of the apparent reversal potential for the pace-maker current iK2 on its degree of activation in cardiac Purkinje fibres. J. Physiol. 280, 73–74.

Google Scholar

Durrer, D., van Dam, R. T., Freud, G. E., Janse, M. J., Meijler, F. L., and Arzbaecher, R. C. (1970). Total excitation of the isolated human heart. Circulation 41, 899–912. doi: 10.1161/01.cir.41.6.899

CrossRef Full Text | Google Scholar

Engelmann, T. W. (1877). Vergleichende untersuchungen zur lehre von der muskel- und nervenelektricitat. Pflueg. Arch. 15, 116–148. doi: 10.1007/bf01628342

CrossRef Full Text | Google Scholar

Franz, M. R. (1983). Long-term recording of monophasic action potentials from human endocardium. Am. J. Cardiol. 51, 1629–1634. doi: 10.1016/0002-9149(83)90199-6

CrossRef Full Text | Google Scholar

Franz, M. R. (1996). Mechano-electrical feedback in ventricular myocardium. Cardiovasc. Res. 32, 15–24. doi: 10.1016/0008-6363(96)00074-0

CrossRef Full Text | Google Scholar

Haissaguerre, M., Jais, P., Shah, D. C., Takahashi, A., Hocini, M., Quiniou, G., et al. (1998). Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N. Engl. J. Med. 339, 659–666. doi: 10.1056/NEJM199809033391003

PubMed Abstract | CrossRef Full Text | Google Scholar

Hansen, B. J., Li, N., Helfrich, K. M., Abudulwahed, S. H., Artiga, E. J., Joseph, M. E., et al. (2018). First in vivo use of high-resolution near-infrared optical mapping to assess atrial activation during sinus rhythm and atrial fibrillation in a large animal model. Circ. Arrhythm. Electrophysiol. 11:e006870. doi: 10.1161/CIRCEP.118.006870

PubMed Abstract | CrossRef Full Text | Google Scholar

Hoogendijk, M. G., Opthof, T., Postema, P. G., Wilde, A. A., de Bakker, J. M., and Coronel, R. (2010). The Brugada ECG pattern: a marker of channelopathy, structural heart disease, or neither? Toward a unifying mechanism of the Brugada syndrome. Circ. Arrhythm. Electrophysiol. 3, 283–290. doi: 10.1161/circep.110.937029

PubMed Abstract | CrossRef Full Text | Google Scholar

Hoogendijk, M. G., Potse, M., Vinet, A., de Bakker, J. M., and Coronel, R. (2011). ST segment elevation by current-to-load mismatch: an experimental and computational study. Heart Rhythm. 8, 111–118. doi: 10.1016/j.hrthm.2010.09.066

PubMed Abstract | CrossRef Full Text | Google Scholar

Janse, M. J., Van Capelle, F. J. L., Morsink, H., Kléber, A. G., Wilms-Schopman, F., Cardinal, R., et al. (1980). Flow of “injury” current and patterns of excitation during early ventricular arrhythmias in acute regional myocardial ischemia in isolated porcine and canine hearts. Evidence for two different arrhythmogenic mechanisms. Circ. Res. 47, 151–165. doi: 10.1161/01.res.47.2.151

CrossRef Full Text | Google Scholar

Jervell, A., and Lange-Nielsen, F. (1957). Congenital deaf-mutism, functional heart disease with prolongation of the Q-T interval and sudden death. Am. Heart J. 54, 59–68. doi: 10.1016/0002-8703(57)90079-0

CrossRef Full Text | Google Scholar

Kléber, A. G., and Riegger, C. B. (1987). Electrical constants of arterially perfused rabbit papillary muscle. J. Physiol. 385, 307–324. doi: 10.1113/jphysiol.1987.sp016495

PubMed Abstract | CrossRef Full Text | Google Scholar

Kohl, P., Day, K., and Noble, D. (1998). Cellular mechanisms of cardiac mechano-electric feedback in a mathematical model. Can. J. Cardiol. 14, 111–119.

Google Scholar

London, B. (2001). Cardiac arrhythmias: from (transgenic) mice to men. J. Cardiovasc. Electrophysiol. 12, 1089–1091. doi: 10.1046/j.1540-8167.2001.01089.x

PubMed Abstract | CrossRef Full Text | Google Scholar

Lown, B., Amarasingham, R., and Neuman, J. (1986). Landmark article Nov 3, 1962: new method for terminating cardiac arrhythmias. Use of synchronized capacitor discharge. By Bernard Lown, Raghavan Amarasingham, and Jose Neuman. JAMA 256, 621–627. doi: 10.1001/jama.256.5.621

PubMed Abstract | CrossRef Full Text | Google Scholar

Lüderitz, B. (2002). History of the Disorders Of Cardiac Rhythm. Armonk: Futura Publishihg Company.

Google Scholar

McGuire, M. A., de Bakker, J. M., Vermeulen, J. T., Moorman, A. F., Loh, P., Thibault, B., et al. (1996). Atrioventricular junctional tissue. Discrepancy between histological and electrophysiological characteristics. Circulation 94, 571–577. doi: 10.1161/01.cir.94.3.571

CrossRef Full Text | Google Scholar

Mines, G. R. (1913). On dynamic equilibrium in the heart. J. Physiol. 46, 349–383. doi: 10.1113/jphysiol.1913.sp001596

PubMed Abstract | CrossRef Full Text | Google Scholar

Mines, G. R. (1914). On circulating excitations in heart muscles and their possible relation to tachycardia and fibrillation. Trans. R. Soc. Can. Sect. 4, 43–53.

Google Scholar

Opthof, T. (1988). The mammalian sinoatrial node. Cardiovasc. Drugs. Ther. 1, 573–597. doi: 10.1007/bf02125744

PubMed Abstract | CrossRef Full Text | Google Scholar

Opthof, T., Coronel, R., Janse, M. J., and Rosen, M. R. (2007). A wedge is not a heart. Heart Rhythm 4, 1116–1119. doi: 10.1016/j.hrthm.2007.05.027

CrossRef Full Text | Google Scholar

Remme, C. A., Verkerk, A. O., Nuyens, D., van Ginneken, A. C. G., van Brunschot, S., Belterman, C. N., et al. (2006). Overlap syndrome of cardiac sodium channel disease in mice carrying the equivalent mutation of human SCN5A-1795insD. Circulation 114, 2584–2594. doi: 10.1161/circulationaha.106.653949

PubMed Abstract | CrossRef Full Text | Google Scholar

Rivaud, M. R., Delmar, M., and Remme, C. A. (2020). Heritable arrhythmia syndromes associated with abnormal cardiac sodium channel function: ionic and non-ionic mechanisms. Cardiovasc. Res. 6:cvaa082. doi: 10.1093/cvr/cvaa082

PubMed Abstract | CrossRef Full Text | Google Scholar

Sanchez-Alonso, J. L., Bhargava, A., O’Hara, T., Glukhov, A. V., Schobesberger, S., Bhogal, N., et al. (2016). Microdomain-specific modulation of L-Type calcium channels leads to triggered ventricular arrhythmia in heart failure. Circ. Res. 119, 944–955. doi: 10.1161/CIRCRESAHA.116.308698

PubMed Abstract | CrossRef Full Text | Google Scholar

Schwartz, P. J., Verrier, R. L., and Lown, B. (1977). Effect of stellectomy and vagotomy on ventricular refractoriness in dogs. Circ. Res. 40, 536–540. doi: 10.1161/01.res.40.6.536

CrossRef Full Text | Google Scholar

Shaw, R. M., and Rudy, Y. (1997). Electrophysiologic effects of acute myocardial ischemia. A mechanistic investigation of action potential conduction and conduction failure. Circ. Res. 80, 124–138. doi: 10.1161/01.res.80.1.124

CrossRef Full Text | Google Scholar

Shivkumar, K., Ajijola, O. A., Anand, I., Armour, J. A., Chen, P. S., Esler, M., et al. (2016). Clinical neurocardiology defining the value of neuroscience-based cardiovascular therapeutics. J. Physiol. 594, 3911–3954. doi: 10.1113/JP271870

PubMed Abstract | CrossRef Full Text | Google Scholar

Travnickova, E. T. S. (1987). Jan evangelista purkyne (Purkinje) 1787-1869. NIPS 2, 232–235. doi: 10.1152/physiologyonline.1987.2.6.232

CrossRef Full Text | Google Scholar

Waller, A. D. (1887). A demonstration on man of electromotive changes accompanying the Heart’s Beat. J. Physiol. 8, 229–234. doi: 10.1113/jphysiol.1887.sp000257

PubMed Abstract | CrossRef Full Text | Google Scholar

Waller, A. D. (1910). Physiology the Servant of Medicine (Chloroform in the Laboratory and in the Hospital). London: Hodder and Stoughton.

Google Scholar

Weidmann, S. (1951). Effect of current flow on the membrane potential of cardiac muscle. J. Physiol. 115, 227–236. doi: 10.1113/jphysiol.1951.sp004667

PubMed Abstract | CrossRef Full Text | Google Scholar

Zhang, J., Sacher, F., Hoffmayer, K., O’Hara, T., Strom, M., Cuculich, P., et al. (2015). Cardiac electrophysiological substrate underlying the ECG phenotype and electrogram abnormalities in Brugada syndrome patients. Circulation 131, 1950–1959. doi: 10.1161/circulationaha.114.013698

PubMed Abstract | CrossRef Full Text | Google Scholar

Keywords: cardiac electrophysiology, extradisciplinary research, multidisciplinary research, history, future

Citation: Coronel R (2020) The Future of Physiology: Cardiac Electrophysiology. Front. Physiol. 11:854. doi: 10.3389/fphys.2020.00854

Received: 29 April 2020; Accepted: 25 June 2020;
Published: 15 July 2020.

Edited by:

George E. Billman, The Ohio State University, United States

Reviewed by:

Crystal M. Ripplinger, University of California, Davis, United States
Vadim V. Fedorov, The Ohio State University, United States

Copyright © 2020 Coronel. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: R. Coronel, rubencoronel@gmail.com