George Ralph Mines (1886–1914): the dawn of cardiac nonlinear dynamics

On 6–7 November 2014, a symposium entitled Cardiac Arrhythmias: Challenges for Diagnosis and Treatment, organized by the authors of this editorial (Fig. 1), was held at McGill University in Montreal to commemorate the centenary of the death of George Ralph Mines (Fig. 2), a Cambridge graduate who at the time of his death, on 7 November 1914 at the age of 28, was the Professor of Physiology at McGill. Inspired by Mines's seminal papers published in 1912–1914, the symposium focused on identifying areas in which basic physiology and theoretical modelling are defining new approaches to clinical cardiac electrophysiology. This special issue contains 11 papers contributed by speakers at this symposium, as well as three other contributed papers and one perspective. Despite his early death, Mines made transformational contributions to cardiac electrophysiology. His research concerning induction of tachycardia and fibrillation provides much of the basis for our current understanding of these phenomena. Mines's papers contain other insights concerning cardiac dynamics that have particular significance in light of subsequent developments in studies of cardiac electrophysiology and dynamics. In this essay, we briefly review Mines's contributions to the study of cardiac electrophysiology and nonlinear dynamics, including some of his lesser known, but very relevant, findings. The mechanisms by which cardiac arrhythmias are initiated, maintained and terminated can be understood in terms of the four basic phenomenological properties of excitability, refractoriness, automaticity and conduction. The heart is thus fundamentally a nonlinear system, since the first three of these properties arise only in nonlinear systems. One of the characteristic properties of many nonlinear systems is bistability, in which at any given time the system can show one of two possible stable behaviours. We describe below Mines's work on three different forms of bistability that appeared just over a hundred years ago in a pair of remarkable articles, one of them in this journal (Mines, 1913, 1914). We then indicate how Mines's pioneering ideas are of relevance to work carried out on cardiac arrhythmias during the century following his death. In his 1914 article, which appeared after his death, Mines showed that the delivery of a premature stimulus to the ventricles of a Langendorff-perfused rabbit heart at room temperature could throw the ventricles into fibrillation for a period lasting ‘from a few seconds up to over three hours’. Mines noted that the stimulus had to be ‘properly timed’. Figure 3 reproduces Mines's kymograph recording of ventricular contraction, with the white spots indicating the times at which an electrical stimulus was applied to the ventricle. While the first six stimuli did not provoke ventricular fibrillation, the last one, arriving at the ‘critical instant’ did induce fibrillation. Mines noted that ‘stimuli too early or too late are ineffective in producing fibrillation’ and that ‘the critical instant for the production of fibrillation is immediately after the close of the refractory phase.’ This period was later termed the ‘vulnerable period’ and the clinical correlate of this behaviour is the ‘R-on-T-phenomenon’, when a premature stimulus or a premature ventricular contraction that induces ventricular fibrillation falls during the T-wave of a normal sinus beat on the electrocardiogram (Ferris et al. 1936; Wiggers & Wégria, 1940; Smirk, 1949). The ventricles of the heart thus support two stable behaviours (normal sinus rhythm and ventricular fibrillation) and there is thus bistability. Injection of a much larger electrical stimulus can defibrillate the heart, i.e. get rid of ventricular fibrillation, thus restoring normal sinus rhythm (Prevost & Battelli, 1899; Gurvich & Yuniev, 1947). This result provides another demonstration of the underlying bistability but in the reverse direction. Two definitions are needed in order to appreciate the major mechanism for the induction of tachycardia and fibrillation. If a stimulus is delivered to a ring of excitable tissue, then in some cases the circulation of excitation may block in one direction, but not the other, leading to unidirectional block. Re-entry refers to a circulating excitation where the period of the rhythm is set by the time it takes to traverse a circuitous path, rather than the period of a pacemaker. A re-entrant rhythm can be generated not only by excitation traveling in a one-dimensional ring, but also by spiral waves circulating in a two-dimensional surface, or wavefronts of more complicated geometries (e.g. scroll waves) circulating in three dimensions. Mines also showed that a circus movement could be produced in rings of cardiac tissue (Mines, 1913, 1914). Mines explained: (i) why unidirectional block was required to start up re-entry, (ii) why there was a vulnerable period during which a well-timed stimulus would initiate re-entry, (iii) why the circumference of the ring had to be shorter than the ‘wavelength’ of the circulating impulse, and (iv) how a well-timed stimulus could abolish the re-entrant motion (see Boukens & Janse (2013) and Aguilar & Nattel (2016), in this issue, for a review). In the case of circus-movement re-entry taking place in the intact heart, one would have bistability between two periodic rhythms: normal sinus rhythm and the re-entrant rhythm that produces a monomorphic tachycardia. As in the case of circus-movement re-entry, the start-up of spiral-wave re-entry by a premature stimulus hinges on there being unidirectional block (Frazier et al. 1989). (See, e.g. movie at http://www.medicine.mcgill.ca/physio/guevaralab/Xu_Movies/homog.mpg, which shows the start-up of a spiral wave by a premature extrastimulus in an ionic model of a two-dimensional sheet of ventricular cells.) While Mines is generally credited with the discovery of circus movement re-entry in cardiac tissue, the first, albeit brief, description of this phenomenon in the heart was in fact by Alfred Mayer, a marine biologist who is widely credited for his systematic studies of the same phenomenon in the jellyfish (e.g. Mayer, 1906, 1908). This fact has been only very occasionally noted in the literature (e.g. Rytand, 1966). Mayer initiated re-entry in ring-shaped strips cut from the turtle ventricle using electrical or mechanical stimulation, and clearly stated the requirement of producing unidirectional block to initiate re-entry (Mayer, 1908). Also, Garrey, in his 1914 report on fibrillation, expressly mentioned that he had conducted public demonstrations in Woods Hole of ‘circus contractions’ in rings of tissue cut from turtle ventricles before the appearance of Mines's 1913 paper (Garrey, 1914). Clinical cardiac electrophysiology identifies physiological and anatomical factors that lead to the induction, stabilization, destabilization and termination of re-entrant tachyarrhythmias. Atrial fibrillation refers to the rapid disorderly activation of the atria leading to a loss of atrial pumping activity. While atrial fibrillation itself is not fatal, its incidence in the population increases with age and it is the most common cardiac arrhythmia requiring medical attention. In this issue, as Haissaguerre et al. (2016) and Narayan & Zaman (2016) discuss, although it is generally accepted that atrial fibrillation is due to re-entrant rhythms, it is controversial whether there is a single ‘mother rotor’ (Jalife et al. 2002), multiple re-entrant wavelets (Konings et al. 1994), or multiple transient spiral-waves (Haissaguerre et al. 2016, in this issue). Since a major clinical objective is to develop techniques to treat atrial fibrillation by ablating atrial tissue, the distinctions are not only of academic interest. Early surgical methods for treating atrial fibrillation, which have also been theoretically modelled (Dang et al. 2005; Jacquemet 2016 in this issue), involved disrupting anatomical regions that could support re-entrant circuits. Noting that the junctions between the pulmonary veins and the left atrium often display rapid activity, Haissaguerre pioneered techniques of ablation to isolate the electrical activity in the pulmonary veins from the atria. More recently, as Narayan & Zaman (2016) discuss in this issue, it has been found that ablating atrial tissue at the central ‘core’ of atrial spiral waves can abolish atrial fibrillation. Whereas Mines observed re-entry by seeing the circulation of a wave of contraction in a ring of cardiac tissue, new technologies that enable mapping the electrical activity in the atria provide an important direction for current work (see Proietti et al. 2016 in this issue). Ventricular tachyarrhythmias, rapid rhythms originating in the ventricles, provide a different set of challenges to clinicians and basic scientists. In patients who have had a myocardial infarction, ventricular tachycardia is often mediated by anatomically defined re-entrant pathways. There are however other possibilities, as discussed by Narayan & Zaman (2016) in this issue. If a wave of excitation leads to a sufficiently strong cardiac contraction, the heart may still pump enough blood to the body so that the arrhythmia would not be fatal, and patients could seek medical treatment. If there is a well-defined anatomical circuit, an appropriate ablation could eliminate the possibility of re-entry and thus prevent the initiation of the arrhythmia (Aliot et al. 2009). In this issue, Proietti et al. (2016) review current approaches and provide a prospective towards ablation of ventricular tachycardia. In contrast with atrial fibrillation, ventricular fibrillation, an irregular rhythm believed to be associated with multiple re-entrant waves, is Since ventricular fibrillation can often be to normal sinus rhythm by an electrical e.g. with an a major is how to methods for so that is to patients who would have a as discussed by & (2016) in this issue. In there can be a from sinus rhythm to ventricular fibrillation, or there can be a ventricular tachycardia. and studies are being towards techniques for by the or by multiple et al. et al. & Mines's on the induction of re-entrant rhythms have had his in other areas are much but are In this we his stable rhythms observed during periodic of cardiac We observed rhythms by the of the of stimuli to the of (e.g. of a rhythm of two stimuli and one Mines that there could be bistability and and rhythms in the ventricle of the (Mines, by that there was a of over which one could a or a on whether the was or to up that (Fig. a rhythm was this a single well-timed extrastimulus could the rhythm from a rhythm to a a rhythm was this two or three stimuli from the stimulus a rhythm to the of In the of is that over a of of there two possible stable so as the heart and Mines his of the bistability and on the of the refractory period and the fact that the of the contraction with an in heart of in single ventricular many years later support for Mines's for and bistability and et al. In these one could in the rhythm to a rhythm by a well-timed premature The can also be when one increases and the stimulus of the & single ventricular et al. There is at one case in a that a atrial or ventricular extrastimulus can from normal sinus rhythm to block and et al. We discuss how the may be an important but in the induction of ventricular tachycardia and fibrillation. In 1913, Mines in his in this in which cardiac by stimuli or with and has been of late the of much The same could be Since rhythms of ventricular or of the electrocardiogram often the induction of ventricular fibrillation, the of theoretical and clinical study et al. & et al. We first discuss different mechanisms for by In some of his on and Mines noted that ‘the from to from to is not so in that the of its appearance and to some (Fig. Mines's for was that ‘the refractory of some of the from that of other and the at which the new of are by Mines's at the first in during a time at which the was being some to the from to other in thus producing the in the of contraction of the ventricle that is between the times by the first two a of irregular rhythm many Mines the which in the of an rhythm of contraction with a or of the that in rhythm up that in time to In Mines then the the time when the into an rhythm of the of some to the of the the was only with a rhythm being not too after the of this Mines his for as given from who ‘the most is that a larger of tissue when the are than when are and in of the ventricle only to other to Mines on to that not that the of which to to be it would be much to is on a Mines on to mechanism for by a that would a This of a ring of tissue from the of a (Fig. its with a to block of so that there are thus two of the ring A and in A was to the to the mechanical contraction of the ring, and the ring was using the pair of at the of the As the of was there was a from a rhythm the ring to a rhythm in We to this as a since the rhythms in the two are in with one Mines showed that a well-timed extrastimulus applied to during the rhythm would a new rhythm in which A and of the ring on i.e. there two out of rhythms in the two of the Since A and not with different and there at the contraction of the ring, a or Figure shows Mines's of activity in the ring during block and block at the same Mines also mentioned that another well-timed stimulus of a few during the rhythm would then the There was thus bistability between and Mines did not report any these two and can also be in the ventricle with the same that Mines In a study using mapping of the in a ventricular as was first and was later by et al. & block of during in a of the the between the two regions where there are of tachycardia or fibrillation in the & Ventricular fibrillation, which in of the and tachycardia by & A later study using of ventricular has that as was could on after and that that there could be multiple et al. a to was using ablation producing a of that of Mines in that there are regions only was in of the & Ventricular arrhythmias up only had being initiated in areas the but with the incidence of ventricular tachycardia over that of ventricular fibrillation In patients heart who for from two showed during atrial et al. in of these was with a in and of these patients then on to show atrial fibrillation. In this much more work on there is of the of as in Mines's work there is a in the of the at in the ventricle. While Mines did of in an paper (Mines, electrical activity was not in the of and so the mechanisms at the underlying the and rhythms by are not at Mines had that mechanical and electrical could be e.g. that there when there was electrical but mechanical (Mines, In the rhythm of the most possibility is that there was of the in A or on with the other In that in the with there is a in the of the as one the in block. One would an or rhythm in which the from beat to beat at more in the of and a rhythm of block at more In this had Mines been to A and during he would have a rhythm in A and and a rhythm more the very start of the on in his 1913 article, Mines out that mechanism to of the heart being in with another being in not that the in rhythm to be in with one and on to an to this (Fig. Mines a that there be in a single the first towards the possibility of in a single with the of recording of the with a in a a recording can show of (e.g. & this is not of or since there is between in Mines had to some which the ventricle the of the ventricular is at the time not the same so although the the same in which a are to only to the of the tissue to block there be of current from the of the into the of the that could to induce since that current would be in and from beat to beat due to the of a rhythm as its i.e. the of in the central of the would itself in from beat to of the of in single many after Mines's only after it possible in the late to isolate single cardiac and with In single rabbit ventricular at a stimulus there is a and then a as is with and bistability et al. 1989). stimulus there is a with bistability and and there can be a transient of of Mines's in et al. stimulus there is a from to rhythms and then to rhythm et al. the in terms of the in single and the of the of the on the stimulus the in a of tissue up the for very complicated behaviours. the in the of an during block not be in some to these not be but due to with more in rhythm and more in rhythm we are then to a of of a with a rhythm in some of the tissue and a rhythm in some other of the there is for a to e.g. of a of electrical being a single ventricular et al. a a single ventricular a electrical rhythm and of can be into a a electrical rhythm but with of et al. 2009). dynamics provides an of as from a a in the dynamics the as a (e.g. the is In a only the and using an one can that a in which the on a arise out of a rhythm as is & A has also been carried out for mechanical & using this the and the mentioned had been to in the et al. but these behaviours not for in that the and the and one can that be with in that a well-timed premature stimulus the would the rhythm to the rhythm et al. also & In the rhythm is a periodic that out of the rhythm a et al. also in of the model that terms (e.g. et al. and in in which the hinges on et al. In in which there is of the the between of the and the of can lead to a of many of which have been observed in and theoretical et al. & et al. In the by of the ventricle can be due to of and tissue et al. et al. for associated with has also been by in which have been that observed rhythms on the that a is for et al. et al. et al. 2009). In and rhythms have been (see et al. and leading to the that ventricular fibrillation be from a of is very in the ventricle following and following and ventricular There has thus been in using of T-wave as a of (e.g. et al. & of the areas of the ventricle in which there is a in the of the et al. et al. et al. et al. et al. myocardial a premature ventricular contraction the following a or an in can initiate a of or & & & and can be at different times as in a given ventricle & et al. et al. et al. et al. and more so the to ventricular arrhythmias as ventricular tachycardia and fibrillation et al. et al. et al. & As in the on of the ventricle the of block that re-entry during close to the the two regions of where there are et al. et al. The in that is following a or after the subsequent or after an in is due to a from to et al. et al. & As the at the on to block et al. et al. et al. et al. et al. There is thus a very close between the the and the bistability between these two rhythms that is during and that which was by This of Mines has There is also to be an of for a in the initiation of atrial fibrillation et al. 2005; Narayan & 2016 in this issue). The refers to the in which the is This is patients with a have an of cardiac death. The of the significance of the first in & and then in et al. after Mines's death et al. and et al. The may as a of mechanisms that the and during the or the that lead to the of the cardiac that lead to and are Since many have this a on and that the of new et al. As by (2016) and by et al. (2016) in this issue, that lead to of the have been The possibility of identifying provides a new prospective for and as it is that some may lead to arrhythmias only in particular may lead to arrhythmias after of only during activity or There are different mechanisms by which the could lead to As discussed the a in the of block and a and is in of and et al. et al. 2009). is often observed in patients with understanding the physiological mechanisms underlying this phenomenon an important research direction et al. In of the can also lead to early of the If an early in a of the heart leads to a this a in the induction of arrhythmia et al. the re-entrant mechanisms by of the of in patients with cardiac death are with this possibility et al. The Mines symposium also areas in which new technologies are of that not by We briefly discuss and The generally refers to the of to and In many single are associated with In the of the is also an on clinical 2016 in this issue). We that that to arrhythmias or other of heart may also in identifying appropriate for a given The of can also be to the dynamics of arrhythmias in with a to and & 2016, this issue). The of for and the possibility for the of into the physiological and anatomical for arrhythmias in of the and body et al. into the anatomical underlying in This provides methods for for ablation that are to mapping In a in this issue & (2016) describe how one can with to the for ventricular tachycardia and fibrillation and to in the Jacquemet (2016) modelling of six different for ablation in atrial fibrillation. The as one approaches a have been very in two using that are of et al. 2016 in this and of a et al. In a on the in this issue, & (2016) that of cardiac be in of patients at for cardiac death. The of cardiac activity at the tissue or have the of and these techniques to be with or and recording be carried out over of the two the study of cardiac electrical activity and the of arrhythmias in the intact heart and in model cardiac systems have from the of mapping of excitation using and there are with this due to the properties of these and a of our to the dynamics of these systems by electrical activity. the has been which the of tissue to that can et al. 2005; et al. 2005; et al. In and have been that recording of electrical activity from cardiac As discussed by & (2016) in this issue, the of new methods for and the for insights into cardiac excitation wave dynamics. In modelling of ionic has been a In this issue, et al. (2016) describe the of and to out model The of electrophysiology is a of the work on of anatomical While there has been in treating heart the of heart has as a to heart and treat heart but there concerning is involved in the most common of heart in which myocardial cardiac As & (2016) discuss in this issue, there have been multiple in an to tissue in While out the with the also the for the of In in the hundred years since Mines's death, there has been a of in our understanding of cardiac electrophysiology and of cardiac While Mines's ideas the vulnerable period and re-entrant rhythms the his on bistability and on rhythms and are much well the of in that of the much more we have at in terms of the of these rhythms, and Mines's insights very well studies to our understanding of these behaviours. The of the first of the was by with subsequent and by and authors have the of the and to be for of the as authors for and who for are for the Mines was by the of and the of Physiology at McGill as well as by the is a research the This work was by a from the and to and We to for of the symposium, and and for the of the