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Eur J Cardiothorac Surg 2006;29:S178-S187
© 2006 Elsevier Science NL
Review |
a University of Alabama at Birmingham, Division of Cardiovascular Diseases, THT 321 N, University Station, Birmingham, AL 35294, United States
b Arthur Andersen, Chicago, IL, United States
c Option on Bioengineering, California Institute of Technology, Pasadena, CA, United States
d David Geffen School of Medicine at UCLA, Los Angeles, CA, United States
e Division of Cardiothoracic Surgery, Washington University School of Medicine, St. Louis, MO, United States
Received 17 February 2006; accepted 28 February 2006.
* Corresponding author. Tel.: +1 205 934 3897; fax: +1 205 934 1279. (Email: ccoghlan{at}cardio.dom.uab.edu).
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Key Words: Electrophysiology • Excitation • Contraction • Myocardium • Activation • Conduction • Fiber architecture • Myocardial band and spiral • Intercellular matrix
The study of the dissemination of the electrical impulse that triggers the contraction of the myocardial fibers developed before the precise structure and the crucial role played by ventricular architecture and fiber orientation in the mechanical efficiency of the heart had been defined. Thus, attention was focused on the time sequence of arrival of the electrical stimulus at different areas of the ventricular wall, with results that depended on the temporal resolution of the existing methodology and the types of electrodes used. Understandably, no attempts to integrate this information with the pattern of contraction, that is so fundamental in cardiac physiology, took place, except in the broad sense of the effect of bundle branch blocks on synchrony of right and left ventricular contraction.
Modern electrophysiology has made extraordinary progress in the detection, understanding, and therapy of arrhythmias and the application of special modes of electrical pacing to change ventricular contraction in hypertrophic cardiomyopathy and advanced heart failure. Extraordinary advances in multisite recording aided by powerful computers have shed light on the genesis and spread of atrial flutter and fibrillation, and ventricular tachycardia, but such techniques have not been applied to the analysis of how electrical activation can take place in a manner that allows the unique structure of the anisotropic ventricles to function as a ‘spiral’ of superb mechanical efficiency.
Lower [1] pointed to the generally helical course of ventricular muscle. Mall [2] described a series of complex spirals and loops within the human heart, but it was the new approach of Torrent-Guasp [3] of following preferential fiber pathways through the substance of the myocardium rather than dissecting parallel to the surface that led to the current concept of ventricular structure and functional architecture [4]. A novel approach to the understanding of ventricular excitation spread must take into account the current concepts of myocardial structure and orientation and its fundamental influence on ventricular function in health and disease, of myocardial ultrastructure and biochemistry and membrane channel physiology. The exhaustive and painstaking anatomical dissection studies of Francisco Torrent-Guasp in over a thousand hearts of diverse species, carefully prepared in order to dissolve the collagen scaffolding without distorting the preferential linear or laminar pathways, have shown that the heart can be unraveled into a continuous myocardial band that extends from the pulmonary artery to the aorta. This band forms a basal loop in continuity with an apical loop consisting of a descending and an ascending segment, the sequential contraction of which determines the isovolumetric contraction (basal loop), ejection (descending) and ‘isovolumetric relaxation’ (ascending) phases (Fig. 1 ) of the cardiac cycle [4].
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The myocardium consists of three integrated components: myocytes, extracellular matrix, and the capillary microcirculation that services the contractile unit assembly. The extracellular matrix provides a stress-tolerant, viscoelastic scaffold consisting of types I and III collagen that couples myocytes and maintains the spatial relations between myofilaments and their capillary circulation. The collagen framework comprises a myofibrillar mesh and intercellular struts that couple adjacent myocytes and align myofilaments to optimize force development, distribute force within the ventricular walls, and prevent sarcomeric deformation. Within this ‘structural mesh’ lies the intercellular substance composed of proteoglycans in close contact with the sarcolemmal membrane of the myocytes, constituting a chemical matrix of highly polar hydrated molecules with well-defined spatial orientation determined and maintained by interaction with domains of special molecules such as fibronectin that bind to plasma membrane proteins such as integrins that ‘anchor’ cells to their extracellular matrix.
Physiologists have long been aware that the performance of the heart as a muscular pump of non-uniform behavior requires a highly coordinated function that is critically dependent on optimal excitation–contraction coupling. Wiggers [6,7] stated that ‘blood is not merely pressed out by a decrease in ventricular cavity; it is virtually wrung out’, while Sarnoff and Mitchell [8] declared ‘The muscular ventricular walls squeeze down on the contained blood much as one would milk a cow or squeeze a lemon in a clenched fist.’
Modern electrophysiology has been greatly enriched by the advances in the knowledge of the physiology of ion channels and sophisticated methods for the study of genesis and spread of cellular action potentials, and the precise definition of structure and protein composition of contractile and specialized impulse-generating and conducting cells of the heart and their connexin-rich gap junctions. The passive membrane properties of resistance, capacitance and ‘cable properties’ of myocytes have been extensively studied concluding that local inward excitation currents carried by sodium ions in most regions, flow intracellularly along the length of the tissue, carried mostly by potassium ions, and escape across the membrane to flow extracellularly in a longitudinal direction to close the loop and complete the circuit. The outside local circuit current is the current recorded in an electrocardiogram [9].
Classical teaching maintains that activation may be viewed as spreading in the manner of a wave front constituted by dipoles generated by multiple cells activated in synchrony. It has been recognized that this model does not take into account that during ventricular activation more than one wave front is usually present [10]. Ventricular excitation is described as the product of two temporally overlapping functions: endocardial activation and transmural activation. Endocardial activation is guided by the anatomical distribution and physiology of the His–Purkinje system, whose broadly dispersed ramifications, likened to a fractal system of high conduction velocity, depolarize most of the endocardial surfaces of both ventricles within several milliseconds. Furthermore, classical teaching maintains that the activation fronts then move from endocardium to epicardium. Excitation of the endocardium begins at sites of Purkinje-ventricular muscle junctions and proceeds by cell-to-muscle cell conduction in an oblique direction toward the epicardium [10–13].
Electrical excitation is greatly facilitated by the rapidly conducting His–Purkinje system. The microanatomy of the Purkinje cells that are long (150–200 um) and broad (35–40 um) with few loosely arrayed mitochondria, distributed between few linearly aligned myofibrils with few myofilaments and an abundance of lateral and end-to-end gap junctions made up primarily of connexin 43, and aligned to form multicellular bundles in longitudinal strands separated by collagen, are uniquely suited for functioning like a cable. This is in sharp contrast with contractile ventricular myocytes that are long and narrow, with very abundant mitochondria and sarcomeres, plentiful T tubules (absent in Purkinje cells), and only end-to-end gap junctions [9,14]. Gap junctions of the intercalated discs provide low resistance electrical coupling between adjacent cells by establishing aqueous pores (special protein channels) that link the cytoplasm of the adjacent cells allowing movement of ions and small molecules between them.
Gap junctions are considered to permit a multicellular structure such as the heart to function electrically like an orderly, synchronized, interconnected unit and are probably responsible in part for the fact that conduction in the myocardium is ‘anisotropic ’, i.e., with properties that vary according to the direction in which they are measured (as are the remainder of the anatomical and biophysical properties of the myocardium). Usually conduction velocity is three times faster in the direction of the long axis of myocardial fibers than in a direction perpendicular to this long axis [9]. This very result was demonstrated in admirable research on the excitatory process in the mammalian ventricle by Robb and Robb in 1935, when they documented that ‘the anatomical conduction paths lie axially along the direction of muscle bands of the ventricle’, and questioned the hypothesis of radial conduction of activation from endocardium to epicardium [11] later maintained by other researchers [12,13], and to the present day [10].
In an extensive review of personal research in electrophysiology as well as the work of multiple other investigators, Taccardi et al. [15] pointed out that most studies of cardiac electrophysiology had failed to correlate propagation of excitation and architecture of cardiac fibers and had thus failed to acknowledge that spread of excitation, sequence of recovery, time-varying potential distributions, and intra and extracardiac electrocardiograms are strongly affected by the complex orientation of myocardial fibers. By studying epicardial excitation and recovery sequences with 180–1200 unipolar electrograms from the surface of dog hearts and intramural activity by inserting between 6 and 150 multi-electrode needles and displaying sequences of potential distribution maps at 1 ms intervals, they showed that the electrical wave fronts followed the complex intramural pathways of myocardial fibers ‘that wind up in a coil-like manner around a series of toroidal cores’. They emphasized the anisotropic resistivity of heart muscle, and the need to incorporate complex fiber architecture and varying angles at different depths of the ventricular wall and insisted that models of the myocardium should be represented as the superposition of two interpenetrating domains: the intracellular and the extracellular domains.
In addition to the importance of myocardial fiber or trajectory distribution and architecture that have been so completely and precisely described in their anatomical and functional significance by Torrent-Guasp et al. [4], there are important lessons to be learnt from the study of the comparative biology of the conducting system, so crucial in achieving the optimal distribution of electrical activation for the most efficient excitation–contraction coupling and resulting ventricular function.
The His–Purkinje conducting system is a neomorphic development limited to birds and mammals [16,17] whose heartbeat requires rapid dissemination of the impulse. In man it is only subendocardial. In the bird's heart, Purkinje fibers penetrate the entire myocardium. The A-V node is like that of the mammalian heart. The His bundle penetrates the septum and soon divides into a right and left bundle that course subendocardially and send fibers that penetrate the entire thickness of the ventricular myocardium. This allows a hummingbird to have 1500 instantly coordinated ventricular contractions per minute required by its flight pattern, and the canary to have a heart rate of 1000 bpm [16,17]. Larger birds with comparatively less cardiac output requirement such as the peregrine falcon have a heart rate of 347 bpm [18]. In the human heart, Purkinje fibers barely penetrate the inner third of the endocardium.
In the pig, descended from the wild boar that is capable of chasing a lion that tries to attack its young by virtue of the intimidating sustained speed of its chase, Purkinje fibers almost reach the epicardium (providing the ‘almost bird-like ventricular function’ of the wild boar). In the dog, descending from the strategically gifted and intelligent wolf, the Purkinje fibers only extend half way into the ventricular wall thickness [9]. In man, the branching portion of the A-V bundle begins at the superior margin of the muscular interventricular septum, immediately beneath the membranous septum, with the cells of the left bundle branch cascading downward as a continuous sheet onto the septum beneath the noncoronary aortic cusp. The bundle may give rise to a posteroinferior and anterosuperior branch, or may give rise to a group of central fibers or it may present as a network without a clear fascicular division. Anderson and Becker [19] admit that the pattern of branching of the left bundle has been controversial and state that their findings endorse the original study of Tawara which demonstrated a fan-like bundle branch with anterior, middle, and posterior radiations. The right bundle branch continues intramyocardially as an unbranched extension of the A-V bundle down the right side of the interventricular septum to the apex of the right ventricle and base of the anterior papillary muscle [9].
The propagation velocity of the electrical stimulus is 3 m/s (3 mm/ms) in the Purkinje fiber but only 0.3 m/s (0.3 mm/ms) in ventricular muscle along its longitudinal axis [9,20]. Thus, the unique ‘conducting cable’ function of the Purkinje system allows it to rapidly deliver the electrical impulse to the immediate proximity or junction with the contracting myocardial fibers in birds and most probably in pigs, to the inner half of the ventricular wall in dogs and only to the endocardium in the human heart. Torrent-Guasp's anatomical studies reveal that birds and mammals have a similar myocardial band structure encompassing right and left ventricles in the sequentially contracting spiral of remarkable mechanical efficiency.
Comparative biology suggests that the high frequency–low pressure pump of birds has the stimulus delivered instantly to the entire band, allowing heart rates of 1000–1500 bpm. No delay in spread of electrical activation would be possible and no known velocity of spread of electrical signal sufficiently fast to allow such high heart rates. The electrical perturbation capable of opening the fast sodium channels to initiate cellular action potential and allow the sequence of calcium changes responsible for excitation–contraction coupling would have to be delivered directly from the Purkinje fibers to the contracting myocytes, or the immediate vicinity of their cell membrane in order to precipitate the ionic/voltage changes required to set in motion the excitation–contraction process needed to permit coordinated ventricular contractions at very high heart rates.
On the other hand, at the markedly lower normal human heart rates, the upper 98% limit of QRS duration is 116 ms in males and 5–8 ms shorter in females [10,21]. The impulse rapidly distributed by the Purkinje system would have to advance from the superficial part of the endocardium to the contractile muscle band in a way that would allow the sequential activation of the basal loop (right–left) followed by the descending segment and lastly the ascending segment of the muscle band which Torrent-Guasp et al. [4] have shown to be essential for the phases of cardiac contraction and relaxation that determine the efficient pump function of the heart.
Even if we assume conduction along myofibers (cell–cell via end-to-end low resistance gap junctions) at the maximum longitudinal velocity of 0.3 m/s or 0.3 mm/ms [9], the 80 mm descending segment would require 266 ms and the 130 mm ascending segment would need 433 ms to complete the activation, figures that far exceed the established total durations of the phases of the human cardiac cycle. In the normal human being, the contraction starts about 35 ms after the beginning of excitation and most fibers appear to have entered into contraction by 105 ms [22]. Furthermore, Taccardi et al. [15] have shown with their extensive multisite mapping of electrical activation within the ventricular wall, that the spread of the activation fronts follows complex spiral pathways and not direct linear pathways making it even more difficult for ‘linear direct within myofiber transmission’ to explain the spread of activation in the human ventricular wall from the superficial endocardial location of the Purkinje network to the contracting myocardial fibers in the well-established timing of the phases of the cardiac cycle. Laser scanning confocal microscopy of guinea pig myocardium with ratiometric fluorescent indicator techniques to study the propagation of calcium waves, as calcium transients activate mechanical contraction, has revealed spiral calcium waves in sequences of confocal optical sections [23].
In order to gain a new understanding of the cardiac activation process we must keep in mind both the macroscopic (muscle band with its ‘linear and sheet trajectories of muscle fibers’) and the microscopic (where excitation–contraction ultimately takes place) structure of the heart, both uniquely designed for optimal function [24]. Cardiac contractile myocardial cells or cardiomyocytes, the fundamental ultrastructural units of the cardiac contraction–relaxation cycle, have about half their volume occupied by myofibrils with sarcomeres containing the contractile proteins, and one fourth to one third by mitochondria [14]. Each myocyte is bounded by a complex cell membrane, the sarcolemma, that invaginates to form an extensive tubular network (the T tubules) that ‘extends the extracellular space into the interior of the cell’ and ‘carries depolarizing currents into the myocardial cell’ [25].
The myocytes contain a fine tubular network demarcated by a lipid bilayer rather similar to the sarcolemma, the sarcoplasmic reticulum (SR) from which calcium is discharged, in response to the wave of electrical excitation, the calcium that triggers contraction and into which calcium is actively taken up to initiate relaxation. Myocytes are grouped into branching myofibers, held together by a collagen mesh and its special collagen struts that couple the adjacent myocytes and align myofilaments to optimize force development and distribution within the ventricular wall and form the vitally important scaffold of the myocardium that maintains ventricular shape and fiber orientation for optimal force development. Within this collagen structural mesh lies the intercellular substance containing proteoglycans, in close contact with the sarcolemmal membrane of the myocytes. Proteoglycans constitute large polyanions that bind water and cations, and form a chemical matrix of highly polar molecules with a well-defined spatial orientation determined and maintained by their interaction with special molecular structures such as fibronectin that bind to plasma membrane proteins such as the integrins that ‘anchor and connect’ cells to their surrounding extracellular matrix.
Conduction system fibers in bundle branches and Purkinje fibers are enveloped by a fine fibrous sheath containing a similar matrix. When the fine branching fibers lose their insulating sheath it is not possible to trace the transition between the conduction tissues and the working myocardium [19]. We propose that the terminal Purkinje fibers that ‘connect with the ends of the bundle branches to form interweaving networks on the endocardial surface of both ventricles’ [9] in the human heart or penetrate to varying depths between the contractile fibers in other mammals and birds, may transmit the activation signal to the myocytes through the intercellular matrix, in intimate contact with the sarcolemma and its T tubules throughout the myocardium. The very short distance between the termination of the Purkinje fibers and the contractile myocytes in birds would allow very rapid spread of activation and make possible their very high heart rates. In man with the least penetration of the Purkinje network in the myocardium, excitation would spread progressively between myofibers of varying angles within the mesh that constitutes the preferential pathways of the muscle band or spiral, reaching the epicardial surface with a timing determined by fiber orientation and thickness of the ventricular wall.
Thus, it is not surprising that the earliest site of arrival of activation in the epicardial surface is the anterior free wall of the right ventricle [26], which is very thin and receives the activation through a right bundle that travels ‘intramyocardially as an unbranched extension of the atrioventricular bundle’ [9] to begin its branching over the endocardium precisely underlying this area of the wall. Rapid activation of the thin right portion of the basal loop of the myocardial spiral to initiate the sequential spread along the band or spiral [27,4] and meet the activation front created by the branching network of the left bundle-dependent Purkinje network would make possible the highly mechanically efficient ventricular contraction. The contraction of the basal loop has been described as providing the stiff outer shell [28] which provides the buttress supporting the apical loop or spiral [4] much in the way a stone circle supports the huts of early Celtic builders or the flying buttresses make possible the majestic gothic cathedrals.
A stimulus delivered to excitable myocardial tissue evokes an action potential characterized by a sudden voltage change caused by depolarization followed by repolarization. The upstroke of the cardiac action potential (phase 0) in atrial and ventricular working muscle and His–Purkinje fibers is due to a sudden increase in membrane conductance to sodium. If an externally applied stimulus or a propagating current modifies the electrical potential over an area of membrane sufficiently to cause the conformational changes that open the voltage-gated fast sodium channels, the rapid influx of sodium will change the transmembrane voltage, opening the calcium channels that allow the relatively small calcium entry that triggers the calcium ion release from the sarcoplasmic reticulum, which precipitates myocardial contraction, effectively bringing about excitation–contraction coupling [9].
Only a small electrical perturbation is required in the immediate vicinity of the cell membrane to initiate the cardiac action potential. We propose that the conduction of a propagating current transferred by the His–Purkinje system from the spontaneously discharging normal pacemaker cells to the intercellular matrix could be very efficiently and fairly rapidly distributed throughout the myocardium. The matrix is in widespread contact with all membranes of contracting myocytes and their special tubular system that ‘extends the extracellular space into the interior of the cell’ [14] for the most efficient excitation–contraction coupling.The composition of the intercellular matrix would appear to be particularly suited for the role of an anisotropic conductor. The proteoglycans of the matrix are large polyanions (Fig. 2 ) containing glycosaminoglycans with disaccharide repeating units which have sulfate [-O3SO] and carboxylate [COO–] groups which provide opportunities for hydrogen (proton) bonding and electrostatic interactions, covalently attached to a polypeptide backbone or ‘core protein’. They are held in an interlocking meshwork (Fig. 3 ) of heteropolysaccharides and fibrous proteins such as fibronectin, attached to integrins that span the cell membrane, so that they have a spatial disposition which provides structure and directionality of function and gives the intercellular matrix strength and resilience.
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. Free protons do not exist in solution. Hydrogen ions formed in water are immediately hydrated to hydronium ions [H3O+]. Hydrogen bonding between water molecules makes the hydration of dissociating protons virtually instantaneous. Protons (hydronium ions) have a very rapid mobility in electrical fields that far exceeds that of sodium, potassium and chloride ions, and is much faster than diffusion. This high ionic mobility is due to the phenomenon of ‘proton hopping’ (Fig. 4
) in which short ‘hops’ of protons between a series of hydrogen-bonded water molecules effects an extremely rapid net movement of protons over a long distance. A hydronium ion gives up a proton; a water molecule some distance away acquires a proton becoming a hydronium ion [31].
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Revisiting the theories of electrical activation of the heart may be especially timely as the complexity of ventricular architecture envisioned over more than 300 years, has been firmly reasserted by recent researchers [4,27,32–37] replacing the concept that the left ventricle was a chamber with simple geometrical shape, thin wall and isotropic constitution which prevailed when the previous theories were proposed. Renewed interest in the mechanism of spread of activation seems appropriate at a time when electrophysiologists are pushing the frontiers of recognition and interventional treatment of arrhythmias and are defining the conditions and benefits of biventricular pacing with sophisticated electrode placement and stimulus timing to improve contraction synchrony and mechanical function of the heart in certain patients with severe dysfunction and intraventricular conduction abnormality.
The important advances in technology for activation mapping have contributed mostly to the field of clinical electrophysiology because, in spite of their sophistication, their resolution is far from adequate to test intramural spread of electrical potentials. A 32-site bipolar electrode basket left ventricular mapping catheter has allowed online reconstruction of color-coded endocardial activation maps with the aid of powerful computer programs [38]. This technique has confirmed that endocardial activation time during sinus rhythm is 105 ± 34 ms and has facilitated identification of sites of origin of ventricular tachycardia for therapeutic ablation.
Important questions regarding our current knowledge of electrical activation of the heart have arisen from attempts to improve systolic ventricular function by ‘cardiac resynchronization therapy’ with biventricular pacing in patients with severe heart failure. Between 30 and 50% of these patients have an intraventricular conduction delay, principally LBBB. Biventricular pacing is based on the premise that stimulating late activating regions of the left ventricle normalizes or optimizes left ventricular synchrony with the resultant hemodynamic benefits derived from increased mechanical efficiency of the left ventricle. However, it has become clear that degree of QRS width reduction is not a consistent indicator of optimal resynchronization and hemodynamic improvement [39]. Furthermore, cardiac resynchronization can have benefit even when it results in widening rather than narrowing of the QRS duration. Even more challenging is the fact that approximately 30% of patients in published series fail to respond to resynchronization therapy [40].
Non-contact mapping is the first technology that has allowed global, simultaneous, percutaneous cardiac mapping for unraveling the complexities of electrical activation of the diseased human heart [41]. This technology has demonstrated that the appearance of the surface ECG is not a reliable method for determining left ventricular activation patterns. In many patients with left bundle branch block, the presence of left bundle activation can be demonstrated with non-contact mapping, and conversely, the absence of left bundle branch block does not mean that the left ventricle is activated by a left bundle or that endocardial activation is rapid [40,42,43].
Lambiase et al. [39] have shown by non-contact mapping that failure of resynchronization therapy may result from placement of the left ventricular lead in regions with slow conduction that do not allow the pacing stimulus to spread to the left ventricular myocardium in a timely manner to permit the optimal integration of activation wavefronts resulting from right and left ventricular pacing stimuli. They concluded that reduction in left ventricular activation time translates into a hemodynamic benefit by reducing septal dyskinesia and allowing early papillary muscle contraction that minimizes pre-systolic mitral regurgitation. They found that patients with dilated cardiomyopathy had a significant response to cardiac resynchronization therapy but many of the patients with ischemic heart disease did not. Non-contact mapping revealed homogeneous cardiac conduction in 80% of patients with dilated cardiomyopathy, whereas patients with ischemic cardiomyopathy consistently showed regions of slow conduction, which impaired the results of resynchronization therapy.
In addition to the subset of patients with ischemic heart disease with heart failure worsened by uncoordinated contraction and relaxation due to electrical conduction delay for which resynchronization therapy has been proposed, there is the very important subset with uncoordinated contraction without conduction delay [44]. Mechanical intraventricular dyssynchrony develops in those patients post-myocardial infarction due to regions of akinesis or dyskinesis that cause non-uniform contraction, relaxation, and filling that lead to global systolic and diastolic dysfunction of the left ventricle independent of electrical delay. High resolution digitization of LV cine angiographic silhouettes at 50 frames per second have allowed the construction of maps of endocardial motion from analysis of 45 chords before and a week after surgical reconstruction to improve ventricular geometry. Pressure–volume loops and endocardial motion analysis depicted in Figs. 5 and 6 from a study of 30 patients, show the very important changes of function and synchrony that result from surgical remodeling of ventricular geometry without interventions that alter electrical conduction.
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Modeling electrical activation based on the cellular and tissue properties of the myocardium offers the only rational approach to the understanding of the highly complex events underlying reentrant arrhythmias and fibrillation, of such paramount importance in basic and clinical electrophysiology. Both the intracellular and extracellular domains must be considered in order to fully explore and comprehend electrical as well as mechanical phenomena in the heart. The three-dimensional arrangement of ventricular myocytes profoundly influences the electrical and mechanical functions of the heart. Nevertheless, a major part of analyses of cardiac function have continued to assume that the material properties of the heart are transversally isotropic. This assumption is not consistent with the well-demonstrated structural anisotropy of the heart [45–47]. Myocardial fiber orientation affects not only the sequences of activation, and repolarization, but also the gradient field distribution and the stimulation threshold [48–51].
Computational modeling of re-entrant arrhythmias and fibrillation has become feasible at a far more complex and comprehensive level; thanks to the remarkable advances in efficiency of computer technology and power. Advances will depend on highly precise information on myocyte arrangement in the three-dimensional structure of the ventricles and on innovative techniques for mapping of both transmembrane and extracellular potentials not just on the heart surfaces but also transmurally.
To date, attempts to reconstruct the three-dimensional spread of electrical activation through the ventricular wall using extracellular plunge electrodes have provided relatively coarse global information at best [46,48]. Researchers at the Bioengineering Institute and the Department of Physiology of the University of Auckland, New Zealand, have made significant advances in their efforts to achieve the ‘modeling of total heart function’ [52]. They have developed automated systems for obtaining three-dimensional images of contiguous sites of resin-embedded myocardial specimens by confocal microscopy.
They view the ventricular myocardium as a three-dimensional hierarchy of interconnecting muscle layers. The discrete muscle layers are separated by cleavage planes and coupled by an extensive connective tissue network. There is branching between muscle layers, constituting thin but sparse muscle bridges between layers. Their model represents ventricular myocytes and extracellular space as overlapping domains and cleavage planes as boundaries to current flow. Their research showed that the spread of electrical activation from an intramural point stimulus (a frequently used technique in animal studies) in the LV is highly anisotropic. Propagation was most rapid along the myofiber axis, slower in a transverse direction within the muscle layer and slowest in the direction perpendicular to muscle layers.
In order to record transmembrane potentials, a novel optical probe or optrode has been developed, with seven hexagonally packed optical fibers inserted into a tapered glass micropipette (400 µm outer diameter). Membrane potentials are measured by dual wavelength ratiometry by exciting a membrane potential sensitive dye (di-4 ANEPPS) with excitation light from a water-cooled argon ion laser delivered via the optrode. The dye is delivered via coronary perfusion to the area of myocardium under study. Intramural extracellular potentials are recorded using epoxy-coated plunge needles each containing 12 unipolar silver wire (70 µm) electrodes at 1 mm separation. Smaill et al. [46] have reported preliminary studies in a pig isolated Langendorff-perfused heart preparation so as to allow studies without motion artifact. Intramural extracellular potentials were recorded with needle probes in the anterior LV wall in the anesthetized pig before excising the heart with the needle probes in place. In the in vivo hearts in sinus rhythm, extracellular potentials exhibited a smooth negative deflection of short duration. There was a rapid transmural spread of activation from subendocardium to subepicardium. The extracellular potentials observed in the isolated heart preparation were very similar to those seen for comparable experimental protocols in vivo, but with slower propagation.
Membrane potentials exhibited a rapid upstroke on depolarization, prolonged plateau and slow recovery to baseline during repolarization (Fig. 7 ). The figure shows the intramural transmembrane potentials recorded from the optical probe at six sites in the pig left ventricular free wall in sinus rhythm. The action potentials are ordered by depth below the epicardial surface from top to bottom, obtained at transmural depths below epicardium of 1.9–8.9 mm. Extracellular potentials and optical signals of transmembrane potentials were acquired at 1 kHz and stored. Data were averaged over 8–12 successive heartbeats. The rapid spread of extracellular potentials from endocardium to epicardium during sinus rhythm is particularly significant for the hypothesis of matrix conduction.
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The highly poisonous venom of jellyfish of the species Chironex fleckeri found in the beautiful tropical waters of the Great Barrier Reef in Australia can cause cardiac arrest in 60 s in an adult victim. Studies have been possible in the less threatening Carukia barnesi. Poison administered to piglets caused a surge of adrenergic activation similar to that observed in surviving human victims of C. barnesi hospitalized for emergency treatment. The dramatic and incredibly fast disruption of electrical activity of the heart by Chironex poison has made Coghlan hypothesize that the poison may reach the heart very quickly and alter the biochemical function of the intercellular matrix leading to an almost instantaneous fatal disruption of cardiac electrical activation with cardiac arrest unresponsive to attempted resuscitation measures.
We realize that proposing a new theory may fulfill the brilliant concept of the late Jacob Bronowski: ‘That is the nature of science: ask an impertinent question, and you are on the way to a pertinent answer’. We are keenly aware to always keep in mind the admonition of the mathematician-scientist Karl Popper that ‘when we do research, we never apprehend the truth, we merely reduce the level of our error’ [55], but we follow Albert Einstein's advice that ‘the important thing is to never stop asking questions’.
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