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The Journal of Physiology logoLink to The Journal of Physiology
. 2016 Jan 19;594(9):2377–2386. doi: 10.1113/JP270506

The pioneering work of George Mines on cardiac arrhythmias: groundbreaking ideas that remain influential in contemporary cardiac electrophysiology

Martin Aguilar 1,2,3, Stanley Nattel 1,3,4,5,6,✉
PMCID: PMC4850190  PMID: 26607760

Abstract

George Mines was a pioneering physiologist who, despite an extremely short period of professional activity and only primitive experimental methodology, succeeded in formulating concepts that continue to be of great influence today. Here, we review some of his most important discoveries and their impact on contemporary concepts and clinical practice. Mines’ greatest contribution was his conceptualization and characterization of circus movement reentry. His observations and ideas about the basis for cardiac reentrant activity underlie how we understand and manage a wide range of important clinical rhythm disturbances today. The notions he introduced regarding the influence of premature extrastimuli on reentry (termination, resetting and entrainment) are central to contemporary assessment of arrhythmia mechanisms in clinical electrophysiology laboratories and modern device therapy of cardiac tachyarrhythmias. Refinements of his model of reentry have led to sophisticated biophysical theories of the mechanisms underlying cardiac fibrillation. His seminal observations on the influence of electrolyte derangements and autonomic tone on the heart are relevant to our understanding of the physiology and pharmacology of arrhythmias caused by cardiac pathology. In this era of advanced technology, it is important to appreciate that ideas of lasting impact come from great minds and do not necessarily require great tools.

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Abbreviations

AF

atrial fibrillation

AFL

atrial flutter

ATP

anti‐tachycardia pacing

AV

atrioventricular

CL

cycle length

CS

circuit size

CV

conduction velocity

ECG

electrocardiogram

ICD

implantable cardioverter‐defibrillator

L

length

PS

point singularity

RP

refractory period

VT

ventricular tachycardia

WLLC

wavelength of the leading circle

Introduction

The research career of George Mines spanned a period of about 8 years until his untimely death at the age of 29 in November 1914. Despite this short period of professional activity and the very limited experimental tools at his disposal, Mines succeeded in producing a series of clairvoyant observations and ideas, projecting an influence that continues to be felt today. In this paper, we review some of the most important discoveries made by George Mines and discuss how they influence contemporary concepts and practice in cardiac electrophysiology and clinical medicine.

Circus movement reentry

In 1914, Mines coined the term circus movement to describe his observations in electric ray and frog heart preparations that, upon cessation of ‘rhythmic stimulation’, ‘the heart gave the impression that the beats of the ventricle were caused by those of the auricle […], while these in turn were caused by the ventricle’ (Mines, 1913 a). Building on earlier work by MacWilliam, Mayer and Garrey, Mines cautiously ‘venture[d] to suggest that a circulating excitation of this type may be responsible for some cases of paroxysmal tachycardia as observed clinically’ (Mines, 1913 a). These insightful observations form the basis of the general mechanism now referred to as anatomic reentry, that is, reentry around a fixed anatomic obstacle, a concept with far‐reaching theoretical and clinical implications.

In anatomic reentry, two pathways separated by an anatomic barrier (i.e. with structurally fixed longitudinal dissociation) form a circuit, the size of which is determined by the anatomic perimeter of the obstacle which determines the length (L) of the reentrant circuit (Fig. 1). Mines not only proposed this novel concept but also correctly noted that ‘a slight difference in the rate of recovery of the two divisions’ is a necessary condition for reentry to occur (Mines, 1913 a). In this model, reentry is initiated when an excitatory wavefront enters the circuit and, because of differential electrophysiological properties, is blocked in one of the two limbs allowing antidromic reentry up the blocked pathway (Fig. 1 B and C). Mines also observed that conditions of ‘slow conduction’ and ‘short refractory period’ facilitate reentry, notions that generally hold to this day. In the circus movement model, the reentry cycle length (CL) is given by the ratio of L to the wave's conduction velocity (CV; CL = L/CV). Therefore, for a given CV, the CL is proportional to L; small obstacles sustain very rapid tachyarrhythmias while larger obstacles sustain proportionally slower rhythms. Conversely, for a fixed obstacle, as is the case in most clinically observed reentrant arrhythmias, the CL is inversely proportional to the CV. Finally, because the excitatory front's wavelength is generally shorter than L, anatomic reentry allows for the presence of an excitable gap, the interval between repolarization of the n th and activation by the (n + 1)th reentrant cycle (Fig. 1).

Figure 1. Schematic representation of anatomic reentry in the atrioventricular node .

Figure 1

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A, reentrant circuit with anatomic obstacle of size L formed by fast‐ (full line) and slow‐conducting (dashed line) limbs. Under normal conditions, the fast pathway conducts from the atria to the ventricles; the slow pathway is concealed as the orthodromic wave collides with antidromic excitation from the fast pathway. B, an appropriately timed premature stimulus (arrowhead) is blocked in the fast pathway (which typically has a longer refractory period) but propagates down the slow pathway. C, stable reentry with antidromic conduction up the fast limb and orthodromic conduction down the slow pathway is established; note the presence of an excitable gap (EG; grey zone).

Mines’ concept of anatomic reentry was not only an important theoretical development in cardiac electrophysiology but also had major clinical implications. He was in fact the first to propose atrioventricular reentry as a mechanism of arrhythmia based on Kent's description of muscular atrioventricular connections (Kent, 1913; Mines 1914 a), as elegantly reviewed by Boukens & Janse (2013). Today, these observations remain highly relevant and form the basis of the understanding and management of a group of arrhythmias known as the atrioventricular (AV) reentrant tachycardias (AVRTs). The prototypical example of AVRT is the Wolff–Parkinson–White syndrome, a reentrant tachyarrhythmia in which an accessory AV connection forms a closed circuit with the atria, atrioventricular node and ventricles (Wolff et al. 1930). Furthermore, Mines’ suggestion that discrete pathways within the AV node having different electrophysiological properties might underlie clinical tachycardias established concepts of the determinants of AV node reentrant tachycardia initiation, maintenance and termination that remain the basis for clinical teaching and practice today.

A few years after the publication of Mines’ landmark paper, Lewis showed that atrial flutter (AFL) may originate from circus movement around the inferior and superior vena cava in the right atrium, a fixed anatomic barrier (Lewis et al. 1920). Moreover, it was found that the AFL CL is increased by extending the anatomic obstacle in a canine model (CL proportional to L), as predicted by Mines (Rosenblueth & Garcia Ramos, 1947; Kimura et al. 1954). Similar principles underlie the AV nodal reentrant tachycardias, a group of anatomic microreentrant arrhythmias involving the AV node and perinodal structures that is the most common arrhythmia in young people with structurally normal hearts (Rubart & Zipes, 2008). More recently, several instances of ventricular tachycardia (VT) were shown to originate from anatomic reentry around myocardial scars, especially in patients with ischaemic heart disease (Wellens et al. 1972, 1974, 1976; Josephson et al. 1987, 2014; de Bakker et al. 1988; Pogwizd et al. 1992). Although he was not a clinician, Mines insightfully noted that reentrant arrhythmias ‘would beat at a much more rapid rate than normal’ and that ‘the onset and disappearance of the abnormal rhythm would be abrupt’ (Mines, 1914 a). The rapid rates and abrupt onset and termination are two clinically relevant characteristics of reentrant arrhythmias still used in the evaluation of patients with tachycardia.

Manipulating reentry: resetting, entrainment and anti‐tachycardia pacing

Beyond the description of anatomic reentry, Mines observed that reentry could be ‘easily upset’ or even terminated ‘by the occurrence of an extra systole’ (Mines, 1913 a). This simple observation forms the basis of the modern concepts of reentry resetting and entrainment and anti‐tachycardia pacing (ATP) widely used in clinical electrophysiology laboratories and implanted tachyarrhythmia‐management pacemakers.

In Mines’ circus movement model, an extrastimulus can have one of three effects on reentry: (A) leave the reentry unaffected, (B) terminate the reentry or (C) reset the reentry, depending on the phase of the extrastimulus relative to the reentry cycle and excitable gap (Fig. 2) (Glass & Josephson, 1995; Waldo, 1997; Gonzalez et al. 2003). Resetting of a reentrant arrhythmia (Fig. 3 A) refers to the interaction of an extrastimulus with the reentering wavefront that leads to a less than compensatory pause, as illustrated in Fig. 3 B (Callans et al. 1993). Entrainment refers to continuous resetting of a reentrant tachycardia by pacing faster than the tachycardia cycle length (Fig. 3 C), with return of the initial reentrant tachycardia upon cessation of pacing (Waldo, 1997). While the results of an extrastimulus shown in Fig. 2 A (no effect) and Fig. 2 B (termination) can be observed with other mechanisms of arrhythmia in response to an extrastimulus, the result illustrated in Figs 2 C and 3 C (resetting and entrainment) is a defining characteristic of reentrant arrhythmias with a fixed anatomic obstacle in the presence of an excitable gap.

Figure 2. Effect of an extrastimulus on anatomic reentry .

Figure 2

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A, an extrastimulus (arrowhead) enters the circuit (dashed line) but collides with just‐excited tissue by the reentrant wave, leaving the reentry unchanged. B, an extrastimulus arising at a different phase of the reentry is allowed to enter the circuit; it collides orthodromically with the tail of the reentrant wave and antidromically with the front of the wave, terminating the reentry. C, resetting occurs when the extrastimulus is blocked only in the antidromic limb and is allowed to itself reenter via the orthodromic limb.

Figure 3. Resetting and entrainment of anatomic reentry .

Figure 3

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A, stable anatomic reentry with excitable gap, EG. The electrocardiogram (ECG) shows a stable tachycardia with cycle length CL. B, resetting. An extrastimulus (arrowhead) enters the circuit and is blocked in the antidromic limb only (left). The orthodromic limb is allowed to conduct and resets the tachycardia with a shorter cycle length (star on ECG signal, middle); subsequent cycles return to cycle length CL. C, entrainment. Starting with a reset cycle (left), a second appropriately timed extrastimulus (arrowhead) follows the same resetting dynamics as in B. Continuous resetting entrains the tachycardia with a cycle length shorter than the original tachycardia cycle length CL (stars on ECG signal). Upon cessation of pacing, the reentry cycle length goes back to CL (not shown).

Resetting and entrainment are not only important theoretical properties of Mines’ model of anatomic reentry. The principles of resetting and entrainment are routinely used to diagnose and treat reentrant arrhythmias in patients (Waldo & Henthorn, 1989; Waldo, 1997). As an example, typical atrial flutter (AFL) is a clinically important supraventricular tachyarrhythmia sustained by counter‐clockwise anatomic reentry in the right atrium (Waldo, 1997). During an ablation procedure for AFL, a cardiac electrophysiologist advances mapping and ablation catheters from the femoral vein into the right atrium. The principles of resetting and entrainment can be used to confirm the diagnosis of AFL and identify anatomic locations within the reentrant circuit in order to deliver ablative radiofrequency energy and cure the arrhythmia. Conceptually similar procedures are now available to treat a wide variety of reentrant supraventricular and ventricular tachycardias (Josephson et al. 1978; Almendral, 2013).

The automated implantable cardioverter‐defibrillator (ICD) is a life‐saving device implanted in patients at high risk for sudden cardiac death (Epstein et al. 2008). High‐energy defibrillation shocks are delivered by the ICD when a malignant arrhythmia, usually ventricular tachycardia (VT) or fibrillation (VF), is detected. Although efficacious, ICD shocks are painful, with a non‐negligible number of patients developing post‐traumatic stress disorders, and frequent discharges significantly shorten battery life (Epstein et al. 2008). Over a century ago, Mines reported an experiment on reentrant circuits in which trains of ‘extra stimuli were thrown in’ and he noted that in a number of experiments ‘the wave was stopped’; this was the first description of ATP (Mines, 1914 a). Anti‐tachycardia pacing is a standard function built into modern ICDs, and involves the application of a train of just‐suprathreshold stimuli that terminates VT, obviating the need for high‐energy defibrillation in a significant proportion of cases (Sweeney, 2004). The antiarrhythmic effect of ATP is based on Mines’ circus movement model: the ATP extrastimuli induce wavefronts that enter the reentrant circuit via the excitable gap and disrupt the reentry, terminating the arrhythmia (Fisher et al. 1983).

From anatomic to functional reentry

Mines’ circus movement model served as the basis for the understanding of cardiac arrhythmias until the 1970s, when Allessie et al. published a series of papers that introduced a new framework for understanding cardiac reentry. In experiments on rabbit atria, they observed that reentry can take place in the absence of an anatomic obstacle, and formalized the first theory of functional reentry in cardiac tissue, termed the leading circle model (Allessie et al. 1973, 1976, 1977). Although similar at first glance, there are important differences between Mines’ circus movement and the leading circle model (Fig. 4). In the leading circle formalism, the reentry circuit size depends on the electrophysiological properties of the substrate and not on the dimensions of an anatomic obstacle. Quantitatively, the leading circle circuit size is equal to the wavelength (WL) of the leading circle (WLLC), which is determined by the excitatory wave's conduction velocity (CV) and refractory period (RP; WLLC = CV × RP). Note that with an anatomic obstacle, the WL is generally shorter than the circuit size and the anatomic properties produce an excitable gap. In the leading circle model of functional reentry, changes in RP or CV dynamically modulate the circuit size, which is always set by the WLLC. Potential circuits greater in circuit size (CS) than WLLC (CS > WLLC) will be dominated by the more rapid leading circle of dimension WLLC. Conversely, circuits with CS less than WLLC (CS < WLLC) will extinguish on tissue continuously kept refractory by centripetal wavelets from the leading circle. Thus, the excitatory front always activates just‐recovered tissue, leaving no room for an excitable gap. The lack of excitable gap contrasts with Mines’ circus movement model and implies that leading circle reentry cannot be reset or entrained. In atrial fibrillation (AF), the classical example of functional reentry (Rensma et al. 1988), an excitable gap can clearly be demonstrated (Duytschaever et al. 2001), raising questions about the applicability of the leading circuit model to this arrhythmia.

Figure 4. Differences between the circus movement, leading circle and spiral wave models of reentry .

Figure 4

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Anatomic reentry is around a fixed obstacle and allows for an excitable gap (EG). In the leading circle model, the circuit size is determined by the conduction velocity (CV) and refractory period (RP); the centre of the circuit is maintained refractory by centripetal wavelets from the leading circle. A spiral wave is a curved wavefront with a point singularity (PS) at its tip rotating around an excitable but unexcited core. The length of the arrow at the spiral wavefront represents local conduction velocity.

An alternative conceptual model of functional reentry, the spiral wave theory, was first described in reference to the Belousov–Zhabotinsky chemical reaction (Krinsky, 1966; Zaikin & Zhabotinsky, 1970; Winfree, 1972). The idea that cardiac fibrillation might result from rotors generated by spiral waves was developed via theoretical studies in the former Soviet Union by Krinsky (1966), and later described in the English language literature by Winfree (Winfree, 1983). A spiral wave or rotor is composed of a curved wavefront and corresponding wave‐tail with all phases meeting at a point singularity (PS), which revolves around an excitable but non‐excited core (Gray et al. 1995). Spiral waves do not have a single discrete WL. If the WL is defined as the length of the excitation wave, a spiral wave has a WL that varies depending on the distance from the PS, and (unlike the leading circle concept) does not govern the stability of reentrant activity. Rather, spiral wave propagation properties depend on the sink–source relationship, the relation between the wavefront's excitatory current density (source) and current density need for excitation of the resting cells (sink) (Cabo et al. 1994). A related determinant of spiral wave dynamics is the radius of curvature of the wavefront; the larger the radius of curvature, the faster the local propagation velocity; conversely, the smaller the radius of curvature, the slower the local propagation velocity. Interactions between the wavefront and wavetail lead to complex and non‐linear trajectories of the PS (meandering), wavebreak and generation of daughter waves (Jalife, 2000). Unlike anatomic reentry and the leading circle, the predictions of spiral wave theory cannot be formulated solely in terms of straightforward electrophysiological determinants like conduction velocity and refractory period, but also depend on curvature and sink‐to‐source relationships, which makes it more difficult for clinicians to apply the spiral wave concept directly to understand clinical observations and applications. Nevertheless, the experimental evidence strongly favours the validity of the spiral wave model (Comtois et al. 2005). Interestingly the spiral wave, like anatomic reentry, includes an excitable gap and thus accounts for the observed properties of AF in the absence of an anatomic obstacle.

Mines’ circus movement concept was instrumental in that it characterized the notion of reentry as a mechanism of arrhythmia in conjunction with previous work by MacWilliam, Mayers and Garrey (MacWilliam, 1887; Mayer, 1906; Garrey, 1924). Mines was an important figure in laying the conceptual framework for the subsequent development of the idea of functional reentry formalized in the leading circle and spiral wave models.

Mines and AF

At the turn of the 20th century, AF was being defined as a clinically important entity and linked to human disease (Flegel, 1995). In 1912, Lewis linked the clinical condition of ‘pulsus irregularis perpetuus’ or ‘delirum cordis’ to fibrillation of the atria (Lewis, 1912). Understanding the pathophysiological mechanisms underpinning fibrillatory cardiac activity was a major research objective to which Mines contributed significantly.

In 1896, Engelmann hypothesized that fibrillation was the result of increased myocardial excitability leading to simultaneous independent firing by multiple cardiac fibres (Engelmann, 1896). Winterberg and Lewis formalized these notions into the multiple heterotopic theory of cardiac fibrillation, which rapidly became a dominant concept (Winterberg, 1906; Lewis & Schleiter, 1912). However, the multiple heterotopic hypothesis was short‐lived as it failed to explain two important observations. First, it had been well described that fibrillation usually occurred under conditions of decreased (not increased) excitability, contrary to the heterotopic model (MacWilliam, 1918). Second, Garrey's experiments showed that recovery from fibrillation was inversely related to the mass of fibrillating myocardium, an effect he called the mass effect; thick slices of myocardium sustained fibrillation for long periods of time whereas sufficiently small pieces could not be made to fibrillate (Garrey, 1914), properties unexplained by the heterotopic model.

Mines’ work provided a novel solution to the problem of cardiac fibrillation. Based on experiments in the tortoise heart, Mines hypothesized that ‘reciprocating rhythms’ or circus movement could be the basis of ‘delirium cordis’ (Mines, 1913 a). The Mines model of fibrillation's key feature was that of a wave ‘travelling in closed circuits’ reentering for ‘an indefinite number of times’ around a fixed obstacle (Mines, 1913 a, 1914 a). To link stable reentry to fibrillation, Mines noted that as the reentrant frequency increased, the wave's ‘rate of propagation’ or conduction velocity slowed and the refractory period shortened (Mines, 1913 a). Using these observations, Mines hypothesized that at very rapid activation frequencies, under conditions of depressed conduction and spatially heterogeneous refractoriness, ‘more than one [wave] could exit at one time’ (Mines, 1913 a), a description strikingly similar to the modern concept of fibrillatory conduction. This model accounted for Garrey's mass effect by stipulating that larger substrates harboured a larger number of potential reentrant circuits (Garrey, 1914), although Garrey himself conceived of AF as a consequence of multiple functional reentry circuits not requiring any fixed obstacles (Garrey, 1924).

Mines’ circus movement model became the basis for the leading paradigm of cardiac fibrillation for the first half of the 20th century. In 1959, Moe and Abildskov argued that it would be unlikely for reentrant circuits to be stable enough in time to sustain arrhythmia over several years or even decades, as is observed clinically in the case of AF (Moe, 1959). Using mathematical and experimental models, they proposed the multiple wavelet hypothesis in which fibrillation is the result of multiple wandering wavelets in a mass of tissue sufficient to maintain sustained activity (Moe & Abildskov, 1959; Moe et al. 1964). The multiple wavelet model represented an important conceptual shift: AF was now viewed as a random self‐sustained phenomenon. In this model, the number of wavelets was proportional to the myocardial mass and inversely proportional to the refractory period and conduction velocity, elegantly explaining previous experimental observations (Moe et al. 1964). The multiple wavelet hypothesis was at the origin of the Cox maze procedure for AF rhythm control in which the atria are surgically severed and re‐sutured, decreasing the effective area for wavelet generation (Cox et al. 1991).

More recent experimental and clinical observations are shifting the AF paradigm back to Mines’ original concept of localized reentry with fragmented conduction. Stable, rapid and spatially localized spiral waves have been observed experimentally in dog and sheep ventricular epicardial muscle, and rapidly revolving spiral wave generators can produce electrocardiographic patterns typical of fibrillation (Davidenko et al. 1992; Pertsov et al. 1993; Gray et al. 1995). There is mounting evidence that AF is not a random process as proposed by the multiple wavelet model; spatiotemporal organization with dominant high‐frequency sources in the left atrium has been described (Pertsov et al. 1993). Consistently, a left atrium‐to‐right atrium frequency gradient is present in experimental as well as clinical studies (Mandapati et al. 2000; Mansour et al. 2001). These results support the notion that an organized rapid source, usually located in the left atrium, with fractionated conduction can underlie AF. In a landmark clinical study, Haissaguerre et al. showed that AF is often triggered and/or maintained by localized high‐frequency sources in the pulmonary veins (PVs) (Haissaguerre et al. 1998). Experimental and clinical work suggested that reentry in the muscular bands extending from the left atrium into the PVs might be at the origin of these drivers (Haissaguerre et al. 1998; Hocini et al. 2002; Kumagai et al. 2004). Localized spiral wave‐type reentry has been observed, highlighting the role of local drivers, as hypothesized by Mines, in the pathogenesis of AF (Narayan et al. 2012).

Beyond circus movement: Mines’ other contributions to cardiac electrophysiology

Although Mines is best known for his work on reentrant arrhythmias and fibrillation, he made noteworthy contributions in other aspect of cardiac electrophysiology. While working on cardiac fibrillation, Mines noted that a ‘properly timed’ stimulus ‘would start fibrillation’ in spontaneously beating tissue (Mines, 1914 a). He hypothesized that ‘the stimulus apparently arrives at some part of the ventricular muscle just at the end of the refractory phase and probably before the refractory phase has ended in some other regions of the muscle’, when ‘the critical instant for the production of fibrillation is immediately after the close of the refractory phase’ (Mines, 1914 a). These observations form the basis of the classical concept of the vulnerable period, a term coined by Wiggers and Wegria in 1940 (Wiggers & Wegria, 1940) for the period during which an extrastimulus can initiate fibrillation, and an idea that remains remarkably unchanged to this day (Starmer et al. 1993; DeSilva, 1997). An important clinical application of the vulnerable period concept is that of synchronized electrical cardioversion. Electrical cardioversion is used in clinical medicine to restore sinus rhythm in patients with haemodynamically unstable or drug‐refractory supraventricular or ventricular tachycardias, as well as in patients with AF or AFL in whom rhythm control is desired (Fuster et al. 2006; Zipes et al. 2006). Virtually all modern automated devices synchronize the stimulus with the patient's QRS complex to avoid delivering the high‐energy shock during the patient's T wave, the ventricular vulnerable period, when it could induce fibrillation (Klein et al. 1991). Another ubiquitous practice exploiting this concept is the use of ventricular sensing in pacemaker devices to avoid pacing during the vulnerable phase.

With Einthoven's introduction of the electrocardiogram (ECG) in 1903, physiologists started investigating the basis of the different deflections of the ECG (Einthoven et al. 1913). Mines provided an insightful explanation for the T wave, corresponding to ventricular repolarization, as representing ‘the excitation passing away’ in the ventricles (Mines, 1913 b). Another problem puzzling the physiologists of the time was the absence of ECG deflection corresponding to atrial repolarization, in contrast to ventricular repolarization with a clear signature in the T wave. Mines elegantly proposed that an event such as atrial repolarization ‘is likely to escape notice’ as ‘it must be usually small’ and occur at a time ‘most unfavourable for its recognition’ since ‘it takes place as a rule at the same time as the initial ventricular variation’ (Mines, 1913 b). Modern ECG recordings confirm the atrial T wave (‘Ta wave’) to be visible under specific conditions (Holmqvist et al. 2009). Moreover, Mines pioneered the study of electrolyte disturbances, later shown to be crucial to the electrophysiological derangements of acute ischaemia, by describing the effects of acidaemia on the QRS complex and PR interval (Mines, 1913 b). Mines was also one of the first to describe the effects of acidaemia on myocardial contractility and excitability (Mines, 1913 c).

Finally, Mines clarified the effects of vagal activation on the cardiac action potential and AV node conduction properties. He reported ‘shortening of the duration of the excited state’ (the action potential duration) and ‘lengthening of the AV [atrio‐ventricular] interval’ upon stimulation of the vagus nerve and the opposite effects with sympathetic stimulation (Dale & Mines, 1913; Mines, 1914 b). These observations remain pertinent to the understanding of a wide range of clinically relevant cardiac conduction disorders and rhythm disturbances like AF (Yeh et al. 2007).

Conclusion

Despite the primitive tools at his disposal and his unfortunately too short professional career, George Mines succeeded in developing mechanistic concepts that still underlie important ideas and approaches in modern cardiac electrophysiology. The efforts of pioneering physiologists like Mines laid the groundwork on which subsequent scientists built, with an accelerating rate of innovation that has led to revolutionary breakthroughs in understanding and management capabilities today (Nattel et al. 2014; Nishida et al. 2014). Nevertheless, important challenges in understanding and treating cardiac arrhythmias remain (Nattel et al. 2014), and conceptual breakthroughs like those pioneered by Mines and other great electrophysiology thinkers of the past will be needed to ensure continued progress in the fight against rhythm disorders.

Additional information

Competing interests

None declared.

Funding

This work was supported by the Canadian Institutes of Health Research and the Heart and Stroke Foundation of Canada.

Acknowledgements

The authors thank France Thériault for excellent secretarial support for the manuscript.

Biographies

Martin Aguilar received his BSc in Physics and MD from McGill University. He completed his residency in Internal Medicine at McGill and is now a Cardiology fellow at the University of Montreal, while completing a PhD in Physiology under the supervision of Dr Nattel. His research focuses on understanding the mechanisms of antiarrhythmic drug action and the rational design of optimized antiarrhythmic drugs for the treatment of atrial fibrillation.

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Stanley Nattel received his MD from McGill University, then trained in Internal Medicine, Clinical Pharmacology, Cardiology and cardiac Physiology/Pharmacology. He is Paul‐David Chair in Cardiovascular Electrophysiology at the University of Montreal and Montreal Heart Institute and Editor‐in‐Chief of Canadian Journal of Cardiology. His research focuses on cardiac bioelectricity and remodelling, particularly atrial fibrillation, ventricular proarrhythmia, ion‐channel molecular physiology and mechanisms of disease‐substrate development/drug action. His lab uses molecular, cellular, whole‐animal and theoretical methods to gain insights into clinically relevant basic mechanisms and novel therapeutic targets.

This review was prepared in relation to the symposium “Cardiac Arrhythmias: Challenges for Diagnosis and Treatment. A symposium in honour of George Ralph Mines (1886–1914)”, which took place at McGill University, Montreal, QC, Canada, between 6–7 November 2014.

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