Getting to the heart of rhythm: a century of progress
2022; American Physiological Society; Volume: 102; Issue: 3 Linguagem: Inglês
10.1152/physrev.00043.2021
ISSN1522-1210
Autores Tópico(s)Phonocardiography and Auscultation Techniques
ResumoEditorialGetting to the heart of rhythm: a century of progressCarol Ann RemmeCarol Ann RemmeAmsterdam UMC location University of Amsterdam, Department of Clinical and Experimental Cardiology, Heart Centre, Amsterdam Cardiovascular Sciences, Amsterdam, The NetherlandsPublished Online:17 May 2022https://doi.org/10.1152/physrev.00043.2021This is the final version - click for previous versionMoreSectionsPDF (4 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Abstract Download figureDownload PowerPoint INTRODUCTIONThe heart has forever fascinated humans, from the ancient Egyptians and Greeks to modern day man. Apart from its physiological role, the heart has multiple reflections in language, culture, and belief systems. During historic times, scientists and philosophers considered the heart as the seat of intelligence, emotion, mind, soul, and life. To this day, the heart is still the symbol of love and remains to be associated with emotion and attachment. However, man has also become increasingly aware of the essential role of the heart in maintaining physical life, and our knowledge of its function as well as the consequences of its dysfunction has grown substantially in the last century.The human heart beats over 80 thousand times a day, and the average person's heart may have beaten up to 3 billion times by the age of 80. During the early stages of pregnancy, the heartbeat provides the first visual and auditory sign of life of the fetus. Conversely, the first sound that the fetus is likely to hear is the heartbeat of the mother. How fitting then, that at the "birth" of Physiological Reviews the very first article published in 1921 written by Eyster and Meek (1) addressed "The origin and conduction of the heart beat." In their insightful review, the authors discussed the landmark discoveries made from the mid-19th century on the electrical function of the heart. Now, 100 years later, at the start of the next century of Physiological Reviews, an update on the huge progress made in the "exciting" field of cardiac electrophysiology is warranted. Guided by a number of excellent reviews published in Physiological Reviews since 1921 as well as a large body of literature, I have attempted to provide an overview of the important advances made on the topic (summarized in the timeline presented in FIGURE 1). However, given the huge scale of the developments and scientific accomplishments made in the field of cardiac electrical (dys)function, I apologize up front for any unintentional omissions.FIGURE 1.Timeline of discoveries and innovations (left) as well as publications in Physiological Reviews (right) discussed in this review.Download figureDownload PowerPointA BRIEF HISTORICAL PERSPECTIVEWhile the ancient Egyptians considered the heart as the center of the vascular system, they did not identify specific structures of the heart and defined it as the center of human intelligence, thoughts, and emotions (see Ref. 2). In ancient Greece, Hippocrates in the fifth century BC described anatomical features of the heart and defined the left ventricle as essential for generation of heat and "pleura," the pure air of life and soul (3). He furthermore recognized that cardiac abnormalities could lead to disease and even (sudden) death (3). In the fourth to third century BC, dissections on the human body were performed for the first time in Alexandria, allowing Herophilus to identify the four heart chambers and Erasistratus to describe the pump function of the heart as well as the importance of valves for blood circulation (4). During the Roman era, Galen described the heart as having a thin right ventricle containing blood and a thicker left ventricle containing air, with blood passing between these two chambers through pores in the interventricular septum (see Ref. 2). Galen's theory would remain unchallenged until the 13th century, when the Arab physiologist and physician Ibn al-Nafis described for the first time the pulmonary circulation (5). Following the anatomical descriptions by Andreas Vesalius published in 1538, and those of others, William Harvey (6) demonstrated in 1628 that the heart pumps blood throughout the body, circulating in a continuous flow within a closed system of arteries and veins. In the 18th century, the anatomy of the circulatory system was described in further detail, and the first observations on pharmacology (digitalis) and the cardiac pulse were published [as reviewed by Gowda et al. (7)]. In 1839, Jan Evangelista Purkinje described a net of flat and gelatinous fibers in the subendocardium of the heart, but its functional relevance was not immediately recognized (8–10).The importance of the electrical function of the heart would only be recognized by the mid-19th century. In 1856, Müller and von Kölliker (11) for the first time linked electrical function to contraction in the frog heart. Using a capillary electrometer, Etienne-Jules Marey recorded the first electrogram of the heart in animals in 1876 (see Ref. 12). Astonishingly, Walter Gaskell around this time already surmised that the impulse of the heart originated within the region of the sinus venosus, spreading through the atrium and subsequently the ventricle, following a delay at the atrioventricular junction (see Refs. 9, 10, 13).A successful recording of electrical activity in the human heart had been made by Alexander Muirhead around 1869 (see Ref. 14). However, the first human electrogram has been attributed to Augustus Desiré Waller who in 1887 recorded cardiac electricity on the body's surface using a Lippman electrometer (FIGURE 2, A and B) and light beam to make photographic records on plates mounted on slowly moving train wagons (18). This "demonstration on man of electromotive changes accompanying the heart's beat" (FIGURE 2C) was published in the Journal of Physiology in October 1887 (15) and was witnessed by, among others, Willem Einthoven, who would himself later credit Waller for the first human electrocardiogram. By 1917, Waller (19) had performed over 2,000 electrocardiograms, of which he published a preliminary survey in the Journal of Physiology.FIGURE 2.The development of the electrocardiogram. A–C: A. D. Waller used a Lippmann's capillary electrometer (A) from either electrodes strapped to the front and back of the chest or saline-filled jars in which the hands were placed (B) to measure the first human electrocardiogram (C; t: time; h: cardiograph; e: electrometer). Image is from Ref. 15 and used with permission from Journal of Physiology. D and E. W. Einthoven further improved the capillary electrometer electrocardiogram identifying the various components (A, B, C, and D) of the cardiac cycle (D) and used a mathematical equation to derive from these the P, Q, R, S, and T waves (E) still used today to designate atrial and ventricular activation and repolarization. Image is from Ref. 16 and used with permission from Pflügers Archiv. F–H: at the end of the 19th century, Einthoven developed the string galvanometer (pictured with the first version in his laboratory in Leiden; F), which was later developed into a commercial version (G); the electrocardiogram measured with Einthoven's galvanometer (H) is identical to the P-Q-R-S-T pattern previously derived from the capillary electrometer electrogram depicted in E. Image in H is from Ref. 17 and used with permission from American Heart Journal.Download figureDownload PowerPointIn 1895, Einthoven (16) derived for the first time from the electrocardiogram the five P, Q, R, S, and T waves as we still know them today, representing atrial and ventricular activation and repolarization (FIGURE 2, D and E). Einthoven, considered "the father of electrocardiography," would go on to develop the first electrocardiogram (ECG) machine, a galvanometer recording voltage differences on paper in the early 1900s (see Refs. 12, 14, 17, 20) (FIGURE 2, F–H). In the following century, electrical and anatomical observations would be increasingly linked, providing mechanistic insight into the initiation and propagation of the heartbeat. Further facilitated by technical and methodological innovations, this has provided us with detailed knowledge of the (patho)physiology of cardiac rhythm and associated clinical implications.PINPOINTING THE ORIGIN OF THE CARDIAC IMPULSEIn their 1921 review (1), Eyster and Meek emphasized the importance of certain anatomical structures identified in preceding decades within the heart for the initiation and propagation of the electrical impulse:"The conception of the origin and conduction of the heart beat in mammals now most widely prevalent, is intimately associated with certain recent histological observations, which tend to support the view of an anatomical as well as a physiological separation of those different properties of cardiac tissue, namely, automaticity, conductivity and contractility. The first of these observations was the discovery of His that a separate bundle of tissue crosses the auricular-ventricular junction in the mammalian heart."In 1893 Wilhelm His Jr. identified a conducting bundle between the atrium and ventricle, which would be followed by the discovery of the atrioventricular node by Ludwig Aschoff and Sunao Tawara in 1906 (21). The latter described a "complex knoten" of tissue located at the proximal end of the His bundle at the top of the interventricular septum, and concluded that this structure was key to the conduction of the electrical impulse from the atrium to the ventricle (FIGURE 3A). In 1907, Arthur Keith and Martin Flack (22) identified a region in the heart of a mole near the sinus venosus containing "primitive" fibers similar to those identified by Tawara (21) (FIGURE 3, B and C). As described by Eyster and Meek (1) in their 1921 review:FIGURE 3.A: illustration by S. Tawara of the left bundle branch in the human heart, with k indicating the "knoten" or atrioventricular node located at the proximal end of the His bundle at the top of the interventricular septum. Image is from Ref. 21, and used with permission. B and C: drawings by Keith and Flack with in B the posterior auricular part of the human heart where a indicates the superior vena cava and d the sinoauricular junction; the line between the asterisks represents the line of section of C, in which the sinoauricular region (sinoatrial node) is indicated by the asterisk. Image is from Ref. 22 and used with permission from Journal of Anatomy and Physiology. D: schematic drawing by T. Lewis of the sinoauricular region of a dog heart where electrodes were placed in the various locations indicated by dots (a–o). Recordings from these electrodes (top left, positions indicated by arrows) identified the sinoauricular node (indicated by asterisk) as the site of origin of the electrical impulse, as evidenced by the largest intrinsic signal. Image is from Ref. 23 and used with permission.Download figureDownload PowerPoint"The histological observations of Tawara showed that the bundle is composed of tissue which differs from the usual type of cardiac muscle, and that it forms an extensive system connecting the auricles with the ventricles. The bundle begins above in a network of interlacing fibers of peculiar structure, lying near the base of the interauricular septum above the middle cusp of the tricuspid valve (the auriculo-ventricular node), and ends below in an extensive surface of the two ventricles. The terminal branches are composed of large cells with prominent nuclei, the previously known Purkinje cells.""The presence of a similar collection of tissue in the sulcus terminalis between the superior vena cava and the right auricle (the sinoauricular node) was discovered by Keith and Flack in 1906. The main histological elements of both the auriculoventricular and sinoauricular nodes are slender, interlacing fibers, which stain lightly, contain many elongated nuclei and are imbedded in closely packed connective tissue."Following these anatomical discoveries, a large number of studies explored the electrical basis of impulse generation, providing functional evidence that this sinoauricular (SA; or sinoatrial) node is the pacemaker of the heart. As reviewed by Eyster and Meek (1), these experiments employed either electrograms constructed from leads placed on the body surface or electrodes applied directly to the heart; using the latter method, the origin of the impulse was pinpointed by Thomas Lewis and others (23–25) to the central SA nodal region (FIGURE 3D). In another series of experiments (many performed by Eyster and Meek themselves), it was demonstrated that disrupting SA nodal function (by local application of formalin or cold) or isolating it from the surrounding tissue resulted in an "escape" pacemaker rhythm generated by the region of the auriculoventricular (AV) node (albeit it at a lower frequency), also known as nodal rhythm. Eyster and Meek concluded (1) the following:"Initial activity, as far as we are able to determine it, is normally associated in both the lower vertebrate and mammalian heart with the sinoauricular node. Abolition of the function of this region results in the assumption of the 'primum movens' by that part of the heart containing similar mass of tissue (auriculo-ventricular node), separated by a considerable distance from the normal seat of initial activity.""The heart beat arises in a relatively small area which, because it possesses the property of automaticity to the highest degree, initiates impulses for the rest of the heart. These impulses pass to all parts of the heart by virtue of the property of conductivity and cause contraction of the muscle fibers of the chambers. Removal of the influence of the region of highest automaticity by its destruction, by its functional separation, or finally by reduction of its automatic power by cooling or other means, results in some other region of lower automaticity assuming the function of impulse initiation. Under these circumstances the original "pacemaker" is quiescent or continues to beat at its original rate but without influence upon the remainder of the heart."Based on available literature, Eyster and Meek furthermore summarized (1) that "Delay in the spread of the excitation from the supra-ventricular regions to the ventricles in the mammalian heart apparently occurs, in larger part, in the auriculo-ventricular node." We now know that this AV delay is essential for an optimal sequence of atrial and ventricular excitation and consequent efficient myocardial pump function and additionally protects the ventricular rhythm from very fast atrial rates and potentially lethal arrhythmias. Interestingly, Eyster and Meek concluded that "Conduction of the excitation to the ventricles in the mammalian heart occurs, probably exclusively, by way of the auriculo-ventricular bundle," although they also acknowledged the observation of Kent in 1893 (26) of "an additional bundle of neuro-muscular structure passing across the auriculo-ventricular groove," which in 1914 was described by Kent as "beginning above in a mass of "nodal tissue" lying in the right lateral auricular wall" (1). Eyster and Meek remarked the following:"After severing all auriculo-ventricular connections except this bundle, auricular contractions were found by Kent to be conducted to the ventricles. These findings, so far as we are aware, have not been confirmed, and opposed to them is the result of numerous investigators that severance of the His bundle alone results in auriculo-ventricular dissociation."Today, the bundle of Kent is known as an accessory conduction pathway between atria and ventricles present in a small percentage (0.1 to 0.3%) of the general population, which may cause arrhythmias in certain circumstances, such as for instance the Wolff-Parkinson-White syndrome (27). However, such insights were lacking a century ago due to limited available techniques for detailed electrophysiological measurements, as further discussed below.ACTION POTENTIALS AND ION CURRENTS: THE IONIC BASIS AND FLOW OF RHYTHMIn a footnote on the first page of their 1921 review (1), Eyster and Meek stated the following:"Why the most automatic region should dominate the remainder of the organ and keep in abeyance the automatic power of other regions will probably not be entirely clear until the nature of the "inner stimulus" and the processes that underlie the initiation of the impulse are understood."Resolving this fundamental question would not be possible until a major new development in the electrophysiology field, i.e., that of the introduction of the microelectrode technique. Refined by G. Ling and R. W. Gerard in 1949 (28), glass micropipettes of <0.5 µm in tip diameter and filled with isotonic KCl enabled membrane potential measurements in tissues and single fibers. In 1949, the technique was used by Edouard Coraboeuf and Silvio Weidmann (30) to successfully measure the first cardiac transmembrane action potential from a Purkinje fiber of a dog heart (FIGURE 4, A and B). In their landmark paper, published in the Journal of Physiology in 1951, Weidmann together with Morrell Draper (29) also measured for the first time propagation velocities (using 2 microelectrodes) and furthermore demonstrated the dependence of the action potential on sodium and potassium ions. This work was followed by a host of studies into the ionic basis of the action potential, as reviewed in detail by Cranefield and Hoffman in Physiological Reviews in 1958 (31).FIGURE 4.Intracellular electrode measurements by Draper and Weidmann (1951) in false tendons of the dog heart, slender bundles of the conduction system that traverse the ventricular cavity. A: schematic overview of the recording setup, consisting of a thermostat-controlled bath with built-in specimen chamber and a glass microelectrode for membrane potential measurements. B: monophasic action potential showing a resting membrane potential of around −90 mV and a clear overshoot. Images are from Ref. 29 and used with permission from Journal of Physiology.Download figureDownload PowerPointOf note, both Weidmann and Coraboeuf had previously worked in the laboratory of A. L. Hodgkin and A. F. Huxley in Cambridge, UK, where they had witnessed key developments in the field of cellular electrophysiology (see Refs. 32, 33). Using squid giant axons, Hodgkin and Huxley (34) had developed the voltage-clamp technique to describe the various ionic currents underlying the action potential. Weidmann and others would subsequently apply this technique to identify the contribution of various ion currents to the cardiac action potential [as reviewed in Physiological Reviews by W. Trautwein in 1973 (35)]. The initial upstroke of the action potential is driven by influx of sodium ions leading to membrane depolarization and consequent opening of L-type calcium channels. This allows calcium ions to enter the cell, which in turn facilitates calcium-induced calcium release from the sarcoplasmic reticulum and consequently contraction. Finally, efflux of potassium ions through the delayed rectifier potassium channels restores the resting membrane potential (repolarization) (FIGURE 5A). While initial experiments were performed in tissues, the 1970s and 1980s would see a substantial increase in action potential and ion current measurements in isolated cardiomyocytes, demonstrating differences between cells from distinct regions in the heart, in addition to the identification of ion pumps and exchangers required for maintaining intracellular ionic homeostasis, as recently reviewed in Physiological Reviews by Varró and colleagues (37) (FIGURE 5B). Ultimately, the patch-clamp technique would be extended by Erwin Neher and Bert Sakmann (38) to single channel measurements, allowing the unique opportunity to study ion channel characteristics with molecular precision.FIGURE 5.A: schematic overview of ion homeostasis in the cardiomyocyte. Influx of sodium and calcium ions ultimately induce calcium release from the sarcoplasmic reticulum (SR), which in turn enables contraction. B: main ion currents underlying the various phases of the ventricular action potential: rapid depolarization (upstroke) mediated by inward sodium current (INa) during phase 0; early or rapid repolarization caused by the transient outward current (Ito) during phase 1; phase 2 or plateau phase characterized by inward L-type calcium current (ICaL); final repolarization mediated by the rapid and slow components of the outward delayed rectifier potassium current (IKr, IKs) during phase 3; and finally, phase 4 characterized by the resting membrane potential that is stabilized by the inward rectifying potassium current (IK1). The action potential is closely linked to the intracellular calcium transient (indicated by the dotted line). Figure is reproduced from Ref. 36, with permission from Cardiovascular Drugs and Therapy. C: due to differences in ion channel expression in cardiomyocytes from distinct cardiac regions (atria, ventricles, conduction system, etc.), action potential morphology is heterogenous throughout the heart. The summation of these tightly orchestrated action potentials results in the cardiac electrical cycle, as indicated by the color-coded sections in the action potential traces and the electrocardiogram (ECG). AVN, atrioventricular node; SAN, sinoatrial node; Epi, epicardial; Endo, endocardial; Mid, midmyocardial. Figure is reproduced from Ref. 37, with permission from the American Physiological Society.Download figureDownload PowerPointWhile cardiomyocytes from atrial and ventricular tissue typically display a resting membrane potential of −80 to −90 mV, microelectrode measurements in the SA nodal region showed a more depolarized value of around −65 mV. As reviewed in Physiological Reviews by Hilary Brown in 1982 (39), the development of small SA nodal tissue preparations allowed for voltage-clamp experiments and detailed investigation of the ion currents involved in pacemaking. Originally, the "decay" or deactivation of an outward potassium current (IK2) was considered key to the diastolic depolarization required for action potential generation in SA nodal cells. However, in the late 1970s, technical limitations to earlier experiments were recognized (see Ref. 40), and this current was reinterpreted as the "funny" current (If), which was considered to play an important role in SA activity. The curiously named If had unusual biophysical properties: it comprised a mixed sodium and potassium inward current that was activated upon hyperpolarization of the membrane (41, 42). Seminal work by Brown, DiFrancesco, and Noble subsequently demonstrated that If was increased by adrenaline (43, 44), which is well known to enhance pacemaker activity and heart rate (FIGURE 6, A and B). Nevertheless, as discussed in various Physiological Reviews articles over the years (39, 45, 46), If was unlikely to be the sole player in cardiac pacemaking, and research from the last decades has indeed demonstrated the importance of other ion currents, as well as the so-called "calcium clock" to this process (40). Here, a tightly coupled interplay between the latter and the membrane potential ("membrane clock") is integrated into the "coupled-clock hypothesis": during diastolic depolarization, If together with spontaneous, cyclic calcium releases from the sarcoplasmic reticulum depolarizes the SA nodal cell, subsequently allowing for inward current through sarcolemmal calcium channels to further depolarize the membrane and initiate the onset of the action potential (FIGURE 6C) (37, 46, 47).FIGURE 6.A and B: impact of autonomic agonists on magnitude of the "funny current" (If ; A) and action potential frequency (B) in cardiac sinoatrial node (SAN) myocytes from rabbit. Isoprenaline (Iso; red trace) increases If and consequently accelerates SAN myocyte frequency, while acetylcholine (Ach; green trace) reduces If and decreases SAN frequency. Image is from Ref. 44 and used with permission from the American Physiological Society. C: the "coupled-clock hypothesis" underlying sinus node pacemaking, which involves a close interaction between both membrane and calcium clocks. Top: distinct phases of the sinus node action potential. Bottom: membrane and calcium clock components. During diastolic depolarization (DD), If together with the sodium-calcium exchanger (INCX; resulting from spontaneous calcium oscillations from the sarcoplasmic reticulum, bottom) depolarizes the membrane. Subsequently, during phase 0, inward calcium currents further depolarize the membrane and initiate the onset of the action potential. During phase 3, outward potassium currents repolarize the membrane to the maximal diastolic potential (MDP). Image is from Ref. 37 and used with permission from the American Physiological Society.Download figureDownload PowerPointDetailed electrophysiological studies have furthermore unraveled the complex structure and function of the AV-node (46, 48, 49). Three subregions within the AV-node have been identified, which each display distinct action potential waveforms as well as differential expression of ion channels, including If. The exact location of the "leading" pacemaker site in the AV-nodal region remained a matter of debate, the difficulty being the small size of the (sub)region in question (46, 50). Nevertheless, studies employing pharmacological inhibitors of various ion channels and exchangers have greatly increased our understanding of the mechanisms underlying automaticity in SA and AV nodal cells. Hence, while the anatomical and functional concepts on pacemaking from 1921 are still valid today, technical innovations including patch-clamp analysis have since then unraveled "the nature of the inner stimulus and the processes that underlie the initiation of the impulse" questioned by Eyster and Meek (1).MAPPING OUT THE SEQUENCE OF VENTRICULAR ELECTRICAL ACTIVITYIn his 1906 study, Tawara (21) had shown that the distal branches of the AV bundle extend into two main branches along both sides of the interventricular septum, making connections with the Purkinje network within the subendocardium, correctly identifying Purkinje fibers (already described in 1839) as crucial for impulse propagation into the ventricular musculature (see Ref. 51). As detailed by Eyster and Meek in 1921 (1), different findings had been observed on the pattern of propagation of the impulse throughout the ventricular myocardium. The authors touch on the "deductions as to the course of the excitation wave in the ventricle from analysis of the electrocardiogram" (1), but this area of research was still in its infancy at the time, likely explained by technical limitations in accurately determining the very fast propagation of the electrical impulse:"Having passed the node, the excitation is distributed through the auriculo-ventricular bundle, and probably reaches the ventricular musculature through the extensive Purkinje network. Due to the extensive branching of the auriculo-ventricular conduction system the excitation probably spreads in various directions, and no longer proceeds as a single wave along a circumscribed path.""The spread through this system is rapid, so rapid indeed that it is difficult or impossible to determine very definitely the direction taken by the excitation."Technical improvements and the development of multielectrode needles and grids resolved most of these technical limitations. In their 1970 seminal publication, Dirk Durrer and colleagues (52) employed up to 870 epicardial and intramural electrodes to describe in detail the excitatory pattern of the isolated human heart: from the AV node, the impulse is carried along the fast-propagating Bundles of His and Purkinje fibers into the ventricular myocardium, propagating from endocardium to epicardium with the apex activated (depolarized) first and the base of the right and left ventricle last (FIGURE 7, A and B). In the last decades, these approaches have been complemented by monophasic action potentials as well as high-resolution optical mapping measurements (see Refs. 53, 54). More recently, electrocardiographic imaging has been employed, allowing for noninvasively imaging of epicardial potentials, electrograms, and activation sequences in humans from surface ECG measurements combined with heart-torso geometry obtained from computed tomography (55).FIGURE 7.A and B: isochronic representation of the atrial activation sequence in a human heart (A), and 3-dimensional isochronic representation of the ventricular activation sequence of the human heart (B) based on measurements from up to 870 intramural electrode terminals. Image is from Ref. 52 and used with permission from Circulation. Each color represents a 5-ms interval, as indicated in the color schemes. C: schematic representation of anisotropic conduction in myocardial tissue indicating the location of gap junction proteins and the direction of longitudinal (fast) versus transversal (slow) conduction. LAA, left atrial appendage; RAA, right atrial appendage; Ao, aorta; SCV, superior caval vein; RV, right ventricle; LV, left ventricle.Download figureDownload PowerPointAt the tissue and cardiomyocyte level, basic electrophysiological studies have explored the mechanisms involved in impulse propagation, as reviewed by Kléber and Rudy (56) in Physiological Reviews in 2004 and by Edward Carmeliet in 2019 (57). Up until the 1930s, chemical transmission was considered by many essential for impulse propagation, but the experiments by Huxley, Hodgkin, and Weidmann disproved the chemical in favor of the electrical theory (29, 34, 58). These studies also showed that current can spread from cell to cell, indicating that the myocardium is a functional syncytium. Indeed, later work identified the presence of gap junctions within the intercalated dis
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