VOL 76SEPTEMBER

NO 31987

cAn Officia1 Journalof the American Heart cAssociation, Inc.

FEATURESThe origin of the heart beat: a tale of frogs,jellyfish, and turtles

W. BRUCE FYE, M.D.

ONE OF THE MOST remarkable phenomena of natureis the incessant rhythmic action of the heart. Althoughphysicians and philosophers have proposed theories toexplain the heart beat for centuries, its mechanismremained elusive until a century ago, when a group ofyoung physiologists working with Michael Foster inEngland unraveled the mystery through a series ofelegant experiments. Critical insight into the origin ofthe heart beat came from studies performed on jellyfishby George Romanes, one of Foster's pupils. Althoughthis research was not initiated to elucidate the origin ofthe heart beat, Romanes soon recognized its relevanceto the work of his mentor. Through their efforts, andthose of Walter Gaskell, another of Foster's pupils, thelong debate over the origin of the heart beat was even-tually settled.

Although it was not universally accepted until thepresent century, the myogenic theory of the heart heathas a long tradition. Galen, whose views influencedWestern medical thought for more than a millennium,discovered in the second century that the excised heartof animals often continued to beat for some time. Heasserted, "The power of pulsation has its origin in theheart itself. . . The fact that the heart, removed fromthe thorax, can be seen to move for a considerable timeis a definite indication that it does not need the nervesto perform its own function."'A Although Galen did notdiscuss the mechanism of the heart's automatic activ-ity, he concluded, "The pulsative faculty of the hearthas its source in its own substance."2

William Harvey did not address the origin of the

Dr. Fye is Chairman of the Cardiology Department at the MarshfieldClinic in Marshfield, Wisconsin, Adjunct Associate Professor of theHistory of Medicine and Clinical Associate Professor of Medicine at theUniversity of Wisconsin in Madison, and Clinical Assistant Professorat the Medical College of Wisconsin in Milwaukee. He has had along-standing interest in the literature and history of medicine, thehistory of cardiology, and the development and implementation ofadvances in diagnostics and therapeutics.

Address for correspondence: W. Bruce Fye, M.D., Department ofCardiology, Marshfield Clinic, 1000 North Oak Ave,. Marshfield, WI54449.

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heart beat in his monumental work De motu cordispublished in 1628, but he did discuss the subject twodecades later. Harvey's view reflected the teachings ofAristotle, which held that the blood within the hearttriggered cardiac contraction.3 In his De generationeanimalium, published in 165 1, Harvey explained, "Thepulse has its origin in the blood. . .. the cardiac auriclefrom which the pulsation starts, is excited by theblood."4 Harvey's theory of the heart beat was essen-tially myogenic-nerves played no role in its genesis.The neurogenic theory of the heart beat was elab-

orated by several 17th century anatomists and physi-cians who were investigating the role of nerves incontrolling muscular activity throughout the body.6Englishman Thomas Willis argued that nerves arisingin the cerebellum carried a "nervous liquor" to nervesin the heart walls, which stimulated the heart tocontract.7' 8 This neurogenic theory of the heart beatwas widely accepted as a result of the writings of Willisand his contemporaries.

Experimental evidence was presented, however, thatquestioned the validity of the neurogenic theory of theheart beat. On the basis of animal experiments,Albrecht von Haller concluded in the 18th century thatthe heart beat spontaneously, independent of nervousor other connections. When he removed the hearts fromanimals, Haller found that they continued to beatdespite the severance of nervous connections. Heargued that the heart muscle had intrinsic irritabilitythat was normally stimulated by the flow of blood overthe walls of the organ. Physiologist William Howellclaimed in 1905, that Haller "formulated a clear-cutmyogenic hypothesis which served to mark the begin-ning of a new discussion lasting until the presentday."5' 9

For more than half a century, Haller views about themyogenic origin heartbeat were widely, although notuniversally, accepted, The French physiologist andphysician Cesar Julien Jean Legallois undertook a longseries ofexperiments on the functions of the spinal cord

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during the first decade of the 19th century. From exper-iments in which he abruptly crushed the spinal cord inmammals and found that the heart stopped beating, heconcluded that the heart beat was neurogenic in origin.Legallois's experiments undermined Haller's doctrineand stimulated renewed interest in the heart beat.

Further investigations led to apparently conflictingresults. Benjamin Collins Brodie, a British surgeon,decapitated dogs and rabbits and observed that theirhearts continued to beat. He concluded, therefore, thatthe heart beat was not dependent on the higher nervouscenters. Other scientifically oriented physicians, mostnotably Wilson Philip and William Clift in Britain,John Reid in Scotland, and Marie Jean Pierre Flourensin France, also pursued this area of research in the early19th century. Their animal experiments failed to sup-port Legallois's belief that the heart beat was dependenton the central nervous system, and, specifically, integ-rity of the spinal cord. Controversy persisted. By the1 830s, most British workers continued to accept Hal-ler's myogenic theory, whereas the French favoredLegallois's neurogenic theory.

Simple observation and experiments based ondestruction of the connections of the heart and nervoussystem gradually gave way to more elegant experi-ments during the middle of the 19th century as exper-imental physiology became more sophisticated.Employing new electrical apparatus, continental work-ers studied the effects of electrical stimulation of theheart and nerves to elucidate the origin of the heartbeat. ° The German physiologists Gabriel Valentin,Alfred Volkmann, and Johannes Muller were amongthose who sought to explain the mechanism of the heartbeat. By the middle of the 19th century, most inves-tigators had concluded that, like skeletal muscle, heartmuscle would respond to a wide variety of stimuli suchas heat, cold, trauma, and electricity. The property thatappeared to be unique to cardiac muscle, however, wasits rhythmicity.As understanding of the anatomy and physiology of

the sympathetic nervous system grew, a new theory ofthe origin of the heart beat evolved. A master of vivi-section, French physiologist Francois Magendie care-fully dissected away the sympathetic nerve supply tothe heart and the first dorsal ganglion and found that theheart continued to beat rhythmically. In 1839, RobertRemak, a pupil of Johannes Muller, demonstrated gan-glion cells in the substance of the heart. These cellswere most prevalent in the atria, where is was widelyacknowledged that the cardiac impulse had its origin.After Remak's discovery of ganglion cells in the sinusvenosus of the frog heart, Heinrich Bidder demon-

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strated them at the auriculoventricular junction, andCarl Ludwig identified them in the interatrial septum.

It was proposed that the ganglia in the sinus venosuswere responsible for the heart beat by sending outstimuli at regular intervals. Analogy was drawn to theaccepted mechanism of the automatic nature of respi-ration, which was attributed to periodic stimuli fromnerve cells in the respiratory center. Muller claimed,"The primary cause of the rhythmic contractions of theorganic muscles is connected with the mode of actionof the sympathetic nerve on the muscles; it is not seatedin the brain or spinal cord." He attempted to explain theapparent inconsistencies of earlier observations:

The cause of the rhythm may be in the muscular fibres them-selves, or it may be in the nerves. If it be in the muscular fibres,we must suppose that while the action of the nerves is constant,the muscular fibres of the heart lose for a time their capabilityof contracting, which is restored during a short repose. If thecause of the rhythm have its seat in the nervous fibres, thesusceptibility of the muscle must be persistent; but the currentof nervous principle must. . . be emitted from them so as toact on the muscles only periodically. The hypothesis that theheart each moment, or eighty times in a minute loses its sus-ceptibility of the still constant influence of the nervous principle,and as often regains it, is improbable, from the circumstance thatall other muscles are capable or persistent action if the stimulusbe continued. The second hypothesis, namely, that theexcitability of the heart is persistent, but the action of the nerveson it periodic, is more probably correct. '

Muller went on to describe the discovery of gangliain various organs and tissues and concluded, "Notmerely the larger ganglions of the sympathetic, buteven its ultimate ramifications in the tissues of organs,seem to possess the power of giving rise to periodicmotions, [so] we can understand how the rhythmicmovements of the heart and intestine. . . continuewhen these organs are removed from their connectionsin the body." Thus Muller proposed that the sympa-thetic nervous system was the source of the constantstimulus that acted on the heart to trigger its beat. Thedilemma was "How can the constant motion of thenervous fluid be changed to a periodic motion:" Draw-ing on recent developments in the physics of electricity,Muller drew an analogy between the situation with theheart and what happens when "a constant current ofelectricity meets with an imperfect conductor." Heproposed that a certain amount of nervous energy accu-mulated in the ganglia until it exceeded the critical levelat which a nervous discharge triggered the heart beat.One of the most important discoveries in cardiovas-

cular physiology during the 19th century was the rec-ognition of the effect of the vagus nerve on the heart.The German physiologists Eduard and Ernst Weberdiscovered the inhibitory influence of the vagus nerve

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on the heart in 1845. They showed that electrical stim-ulation of the vagus nerve would slow or even stop theheart beat. 12 On the basis of an extensive series ofsophisticated animal experiments, the Webers con-cluded that the sympathetic nerves were the motornerves of the heart and that they acted through theintracardiac ganglia they innervated. In their opinion,the isolated heart continued to beat because of intrinsicrhythmicity of the cardiac ganglia. The activity of thecardiac ganglia, and therefore the heart beat, was influ-enced by the vagus nerve, which inhibited the ganglia.The Webers' recognition of the cardioinhibitory

influence of vagal stimulation encouraged severalworkers to intensify their investigations of the mech-anism of the heart beat. Initially, it appeared that thediscovery of vagal inhibition lent strong support to thebelief that heart beat resulted from nervous impulsesacting on the muscle. Further insight into the relation-ship of the nervous system and muscles in the cardio-vascular system was provided by French physiologistClaude Bernard, who demonstrated the existence ofvasomotor nerves around 1850. One historian hasclaimed that these discoveries meant "the entire car-diovascular system could now be seen as a sort ofmuscular puppet whose strings were controlled byagents in the sympathetic nervous system. ,13New observations from European laboratories

enabled physiologists to refine their theory of the heartbeat. In 1850, Moritz Schiff demonstrated the phe-nomenon of the refractory period of heart muscle. 14 15Hugo Kronecker and Jules Marey independently con-firmed Schiff's results, and the concept ofthe refractoryperiod gained widespread acceptance. This discoverystrengthened support for the neurogenic origin of theheart beat, since it provided an explanation for itsintermittent nature despite constant nervous impulsesthat originated in the so-called motor ganglia in theheart.

Experiments in which the entire heart or sections ofit were excised to study the results of such interventionson the heart beat became more sophisticated during the19th century as histologic and physiologic techniqueswere refined. In 1852, H. F. Stannius showed that itwas possible to interrupt the heart beat by placing a

ligature between the sinus venosus and the body of theright atrium. By electrically stimulating the tissue near

the auriculoventricular junction, he also demonstratedthat it was possible to restore the rhythmic beat of theheart. These experiments, combined with the discoveryofcardiac ganglia, reinforced the belief that it was theseganglia that controlled the heart beat.'6 Although aclearer picture of the nature of the heart beat was

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emerging, there were still many inconsistencies andobservations that defied explanation. An anonymousreviewer of cardiac physiology asserted in 1860 that theorigin of the heart beat remained "a subject of a verydebatable character, and one on which much remainsopen for investigation."''7 It was in this context that thecareer of Michael Foster began.

Foster studied under William Sharpey, "the father ofmodern physiology in Britain," at University College,London. His interest in the heart beat began early in hiscareer. In 1859, he published a brief note on a studyof the snail in which he discovered that very smallpieces of excised heart continued to beat rhythmicallyfor some time. He concluded that the heart beat was not"the result of any localized mechanism, but is probablythe peculiar property of the general cardiac tissue. 18

While teaching experimental physiology at his almamater, Foster published a summary of his experimentson the effect of interrupted current on the frog ventricle.It had been shown that if the ventricle of the frog's heartwas divided transversely, the apical segment would notbeat spontaneously whereas the basal segment would.The accepted explanation was that ganglia were nec-essary to trigger the heart beat, and these had beendemonstrated in the basal portion of the ventricle butnot in the apex. Foster found that a weak interruptedcurrent applied to the isolated apex produced a seriesof beats "separated from each other by distinct intervalsofcomplete rest." This was in contrast to the effect suchinterrupted current had on skeletal muscle, whichwould be "thrown into tetanus." Based on these exper-iments, Foster drew the important conclusion that "car-diac muscular tissue itself differs for some reason orother from ordinary muscular tissue in a dispositiontowards rhythmic rather than continuous contraction;and that the influence of the ganglia is probably notrhythmic but continuous, whatever the exact nature ofthat influence be."'19

In 1869, Foster delivered a series of lectures at theRoyal Institution of Great Britain, excerpts of whichhave been published by historian Gerald Geison.20Foster's second lecture dealt primarily with the heartbeat. He declared, "The cause of the heart's beat issomewhere in the substance of the heart itself." Fosterwas dissatisfied with the contemporary interpretation ofthe role of the ganglia in stimulating the heart beat:

Now when a physiologist in his searching after the hiddencause of some secret motion finds a ganglion, he cries 'Eureka!'and generally folds his hands as if his work were done. In thecase of the heart, however, we may venture to go a little furtherand ask the question: in what way or by what means are theseganglia the cause of the heart's spontaneous beat? Is it that a

stimulus or disturbance periodically arises in the substance of the

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potent active nerve cells and then hurries down to the muscularfibre as a nervous impulse causing it to contract? Or is it that thestimulus arises in the substance of the muscular fibre, or if youwill, that like the cilia, the heart fibres periodically overflow withenergy and from time to time burst out in action of their ownaccord, but that a conjunction with nerve cells is in some wayor other necessary for the well being and perfect work of themuscle such as would insure the periodical rise of a stimulus oroverflow of energy.

Only through further research could Foster hope toanswer these questions. When he went to Trinity Col-lege, Cambridge, in 1870, Foster established a sophis-ticated program of advanced training and research inphysiology. There, in a long series of elegant exper-iments, Foster and his pupils confirmed the myogenictheory of the heart beat and set the stage for our under-standing of disorders of cardiac impulse formation andconduction. Foster was not alone in his search for theorigin of the heart beat, however. Other investigatorscontinued their work on the innervation of the heart andthe physiology of the heart beat as well.The world's leading center of cardiac physiology in

this era was Carl Ludwig's laboratory at the Universityof Leipzig.2' There, recent Harvard medical graduateHenry P. Bowditch was performing a series of exper-iments under Ludwig's direction. Using the isolatedfrog heart preparation developed in Ludwig's labora-tory, Bowditch demonstrated that, under proper exper-imental conditions, the isolated apex of the frog heartcould be made to beat spontaneously despite theabsence of ganglion cells. According to physiologistChandler Brooks, these experiments represented "thefirst important study of cardiac excitability."22' 23 Stud-ies from Ludwig's laboratory by Bowditch and J.Merunowicz were useful to Foster and his pupils as theycontinued their investigation of the origin of the heartbeat.

With A. G. Dew-Smith, Foster studied the effect ofinterrupted and continuous current on the excised butstill beating snail heart and found that it was possibleto induce rhythmic pulsations that would proceed fromthe atrium to the ventricle. From these experiments,they concluded that the "fibres" of the snail's heart werenot isolated, as was the case in typical skeletal muscle;rather, they were "physiologically continuous; so thatany change set up in any part of the ventricle can bepropagated over the whole of it in the same way thata contraction-wave set going at any point in a striatedfibre is propagated along the whole length of thefibre. "24At about this time, one of Foster's pupils, George

Romanes, began his experiments on the jellyfish-experiments that contributed greatly to the elaboration

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and ultimate acceptance of the myogenic theory of theheart beat.25' 26 Romanes worked in Michael Foster'sphysiologic laboratory with Walter Gaskell and A. G.Dew-Smith in the early 1870s. In 1874, he began astudy of the medusa, or jellyfish, in which he soughtto elucidate the mechanism of the rhythmic contrac-tions of this invertebrate. Independently wealthy,Romanes set up a private biological laboratory at hissummer home at Dunskaith on the Scottish coast.Romanes informed his friend Edward Schifer,

another of Foster' s pupils, "I am working very hard justnow. The medusae have now come on in theirlegion, and occupy my undivided attention. The resultsso far have proved as definite as they are interesting andimportant." The jellyfish, a coelenterate, movesthrough the water in response to rhythmic contractionsof its "iswimming bell," which includes a thin layer ofmuscular tissue with a rim containing "marginal bod-ies." Romanes found he could render the swimmingbell immobile by excising either the strip of differen-tiated marginal tissue that surrounded the bell or all ofthe marginal bodies. This special nature of this mar-ginal tissue was further shown by the discovery that the''severed margin continues its rhythmical contractionsfor two or three days."27 Romanes studied the tissueunder the microscope and concluded the muscular tis-sue was nonstriated and did not seem to contain nerves.These observations led Romanes to conclude that themarginal bodies were responsible for the periodic spon-taneous motion of the swimming bell of the jellyfish.He also showed that although the excised bell of thejellyfish did not contract spontaneously once the mar-ginal tissue was removed, it would contract in responseto mechanical or electrical stimuli. In the course of hisexperiments, Romanes demonstrated that progressivesectioning of the bell would ultimately lead to thedevelopment of "block" of the contractile wave. Thisconcept of "block" would soon recur in Walter Gas-kell's studies on the heart.

In another letter to Schafer, Romanes mentioned:

.you no doubt remember that in the paper we heard Dr.Foster read, he said that, the snail's heart had no nerves organglia, but nevertheless behaved like nervous tissue in respond-ing to electrical stimulation. He hence concluded that in undif-ferentiated tissue of this kind, nerve & muscle were, so to speak,amalgamated. Now it was principally with the view of testingthis idea about 'physiological continuity' that I tried the modeof spiral & other sections mentioned in my last letter. The resultof these sections, it seems to me, is to preclude on the one handthe supposition that the muscular tissue of medusae is merelymuscular (for no muscle would respond to local stimulusthroughout its substance when so severely cut), & on the otherhand, the supposition of a nervous plexus (for this would requireto be so very intricate, & the hypothesis of scattered cells is

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without microscopical evidence here or elsewhere). I think,therefore, that we are driven to conclude that the muscular tissueof medusae, though more differentiated into fibres than is thecontractile tissue of the snail's heart, is as much as the latter, aninstance of 'physiological continuity.'28

A critical link between Romanes's experiments onjellyfish and Foster's on the origin of the heart beat hadtherefore emerged. Romanes concluded that the behav-ior of the muscular tissue of the medusa was strikinglysimilar to that of the snail's heart. He discussed thiswith Foster and informed Schafer that "Dr. Foster fullyagrees with me in this deduction from my experiments,& is very pleased about the latter, thus affording addi-tional support for his views." Romanes believed that"the properties of nerve and muscle are united in thecontractive fibres of medusae." He continued, "Therecan be no doubt whatever that the seat of spontaneityis as much localized in the margin, as the sensibility tostimulus is diffused throughout the bell. There must,therefore, be some structural difference in the tissuehere to correspond to this great functional difference.28Romanes submitted a paper based on his medusa

experiments to the Royal Society because he was con-vinced of their significance and Foster had written him"preaching high morality about it being the duty of allscientific workers to give their results to others as soonas possible."29 After his presentation, Romanesreceived encouragement from a variety of sources.Charles Darwin wrote: "I have just heard that yourlecture was a splendid success in all ways."30 Writing60 years later, Nobel laureate and pioneering neu-rophysiologist Charles Sherrington emphasized the rel-evance of Romanes's experiments on jellyfish to sub-sequent developments in our understanding of theorigin of the heart beat: "Romanes's observations car-ried out with simple means were novel and fundamen-tal. The questions which he put to the swimming-belland answered from it, led, it is not too much to say, tothe development ofmodern cardiology. Medusa swimsby beat of its bell, and Romanes examining it discov-ered there and analysed the two phenomena now rec-ognized world-over in the physiology of the heart, andthere spoken of as the 'pace-maker' and 'conduction-block' ,31

While Romanes was studying medusae, Fosterextended his earlier studies of the effects of electriccurrent on the heart. On the basis of frog experiments,Foster concluded, "The well known, easily recognized,ganglia of the heart play a subordinate part in theproduction of the heart's spontaneous rhythmic pulsa-tions. The real origin of these is to be sought for in thephenomena of muscular tissue." He also showed that

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the isolated apex of the ventricle, although devoid ofganglia, could beat spontaneously. This observationsupported German physiologist Theodor Engelmann'sconcept of the "physiological continuity" of the entireventricle.32 33 Foster summarized contemporaryunderstanding of the origin of the heart beat in hisclassic physiology text, first published in 1877. Heexplained, "The beat of the heart is an automatic action;the muscular contractions which constitute the beat arecaused by impulses which arise spontaneously in theheart itself."34More than anyone else, Foster's pupil Walter H.

Gaskell was responsible for the ultimate acceptance ofthe myogenic theory of the heart beat. Foster served asthe link between his pupils Romanes and Gaskell-information and interpretations were freely sharedbetween the professor and his pupils. Historian JohnLesch has claimed, "Romanes' clear and decisive con-clusions and the analogy he drew between the cases ofthe medusa and the heart were important elements inthe background of Gaskell's later demonstration of themyogenic origin of the heart beat."35

After preliminary education in London, Gaskellentered Trinity College, Cambridge, in 1865. WhenMichael Foster came to Cambridge five years later,Gaskell was attracted to the physiologist's laboratory.As was the case with several other ambitious medicalgraduates interested in physiology, Gaskell also stud-ied with Carl Ludwig in Leipzig. Describing Gaskell'sreturn to Cambridge from Leipzig in 1875, Foster'sbiographer claimed, "Gaskell must have found himselfvirtually surrounded by men at work on beatinghearts."13

In an 1882 paper, Gaskell acknowledged that mostphysiologists still attributed the heart beat of "the actionof certain ganglion cells situated in the heart itself,while the cardiac muscular tissue is credited with thepurely subordinate role of responding to the impulsesgenerated in these nerve cells." After summarizing thedata that refuted this view, Gaskell declared, "Seeinghow insecure is the hypothesis of the existence ofautomatically acting nerve cells. . in the apex of thefrog's heart. . . it is well worth while to considerwhether the phenomena in question may not beexplained by the properties of the muscular tissues perse."36

Gaskell sought to go beyond traditional explanationsof the cause of the heart beat and drew an analogybetween it and glandular secretion, a subject then beingstudied by his colleague John Langley in Foster's lab-oratory. In a lecture before the Royal Society, Gaskellproposed that the heart's muscular protoplasm pro-

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duced an "explosive substance" analogous to the prod-ucts formed in gland cells that led to secretion. Incor-porating Foster's earlier investigations and his ownrecent studies on the function of the vagus nerve intothis scheme, Gaskell suggested that its role was tocontrol the rate of formation of this substance.37 Gas-kell (and Foster) recognized that the heart beat wasaffected by the vagus nerve, the cardiac ganglia, andthe heart muscle itself, but the fundamental cause of therhythmic beat remained obscure.

Significant advances in Gaskell's methods and hisdecision to turn from the frog to the tortoise facilitatedhis research at this point. He had developed a newmethod that enabled him to record separately any minorvariations in the force of contraction of the atrium andventricle of the isolated heart. Gaskell also made useof former Foster pupil H. Newell Martin's recentlydeveloped isolated heart preparation in which the cor-onary arteries were perfused.38 39

Employing these new techniques, Gaskell sought toprove whether separate mechanisms were necessary toexplain the rhythmic properties of the sinus, atria, andvarious segments of the ventricle. He found that theisolated tortoise ventricle "beats automatically with asgreat a certainty as the isolated auricle.'" And, unlikethe frog, no chemical, mechanical, or electrical stim-ulus was necessary for the tortoise ventricle to continueto beat rhythmically. This critical observation led Gas-kell to conclude, "The automatic rhythm of the ven-tricle is of the same kind as that of the auricle, andtherefore as that of the sinus, so that if the latter is dueto the presence of motor ganglia so too is the former,and on the other hand, if the former be due to someinherent rhythmical property of the ventricular muscle,then the latter is due to a somewhat better developmentof the same kind of property in the muscular tissue ofthe sinus."40

Since it was acknowledged that the apex was devoidof ganglion cells, it seemed likely that the musculartissue itself possessed the ability to beat rhythmically.Based on sophisticated experiments in which he studiedstrips of isolated ventricular muscle, Gaskell arguedthat the heart rhythm was "automatic" and "due to somequality inherent in the muscle itself.?" On the basis ofthese experiments he concluded, "Between the rhythmof the sinus and the rhythm of the muscular strip fromthe apex no hard and fast line can be drawn; betweentwo extremes a distinct gradation of rhythmical poweris manifested, and wherever such automatic rhythm isdeveloped the laws of its development are the same.What differences there are, are differences of degreenot of kind."

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Gaskell also sought to explain the orderly sequenceof contraction of the atrium and ventricle. A few yearsearlier, Foster had encouraged Charles Darwin's sonFrancis to investigate the histology of the snail heart.In the course of that study, Darwin made the importantobservation "that there is muscular continuity betweenthe auricle and ventricle."'41 This discovery had sig-nificant implications for Gaskell's study of the con-duction of the cardiac impulse.

Gaskell functionally distinguished two sections ofthe atrium, the "sinus-auricle," the part near the sinusitself, and the "ventricle-auricle," the part of the atriumnear the auriculoventricular groove. He demonstratedthat the direction of contraction was from the "sinus-auricle" to the "ventricle-auricle"7 and from there to theventricle. Gaskell explained, "The ventricle contractsin due sequence with the auricle because a wave ofcontraction passes along the auricular muscle andinduces a ventricular contraction when it reaches theauriculo-ventricular groove." As Gaskell progressivelysectioned the atrium and narrowed the bridge of tissuethat connected the atrium with the ventricle, he dis-covered that instead of a ventricular contraction fol-lowing every atrial beat, the ventricle contracted inresponse to only every second atrial contraction. Bycutting further this narrow bridge of atrial tissue, "thenthe contraction wave is absolutely unable to pass, thenthe 'block' is complete and any contraction of theventricle which may occur are absolutely independentof those of the sinus and sinus-auricle."40

Although Gaskell did not mention Francis Darwin'sobservations, he was certainly aware of them. In anearlier paper, Gaskell had demonstrated that heartblock would occur if this muscular bridge were divided:"If the auricular muscle be carefully separated from theventricle and along each side of the inter-auricular basalwall, so that the ventricle is connected with the sinusand auricle only by the band of tissue which containsthe large nerves and coronary veins, then the sequence[of contraction] between auricle and ventricle isentirely lost; i.e. the sequence does not depend uponthe nerve trunks between sinus and ventricle."'38

In his 1883 paper, Gaskell credited this terminologyof "block" to this friend George Romanes: "In hisexperiments upon the passage of contraction wavesalong the muscular tissue of the swimming bell of theMedusae, Romanes has throughout made usage of theterm 'block' to express any artificial hindrance to thepassage of the contraction. I therefore make use of thesame term in speaking of the results of experiments onthe cardiac muscle which are very similar to thosewhich he performed on the muscle of the medusae."

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Gaskell claimed that his experiments showed conclu-sively that ventricular contraction occurred only afterthe passage of a contraction wave to the auriculoven-

40tricular groove.Gaskell now sought to elucidate the mechanism of

the delay between contraction of the auricle and theventricle "by examining whether any particular portionof the auricles and ventricle is especially concernedwith the maintenance of the sequence of ventricularupon auricular beats, and at the same time investigatingthe structure of the auriculo-ventricular groove." In aseries of elegant experiments, Gaskell proved that thebasal part of the auriculoventricular groove where thesympathetic nerve fibers enter and where ganglion cellsare most prevalent, "has the least share in the main-tenance of the sequence of the ventricular and auricularbeat." Gaskell claimed, "The muscular tissue of thesinus however is not the only rhythmical tissue of theheart. When the sinus is removed regular contractionwaves still pass over the heart which originate from thatpart of the remaining muscular tissue which possessesthe greatest rhythmical power."

Although Geison has recently asserted that this 1883paper by Gaskell marked a "watershed" in the historyof cardiovascular physiology, the long-standing myo-genic-neurogenic debate was not suddenly resolved.Gaskell's comprehensive summary of his experimentson the tortoise heart lent strong support to the myogenictheory of the heart beat, yet some continental physi-ologists continued to favor the neurogenic theory.Resistance to the myogenic theory was gradually over-come as additional investigations were undertaken,and, especially, as morphological studies provided astructural framework for the theory.

Initially, there was reluctance to accept Gaskell'stheory of the heart beat in the frog and tortoise as themechanism in higher warm-blooded animals. Eventu-ally, however, several workers such as Stanley Kentand Rudolf Krehl demonstrated muscular continuity inthe mammalian heart "quite sufficient to account for thepassage of a contraction wave" between the atria andventricles.42' 43 In 1891, British physiologists WilliamBayliss and Ernest Starling showed that the contractionwave in the mammalian ventricle passed from base to

apex just as in the case of the frog and other coldblooded animals. American physiologist William Por-ter of Harvard, best known for his classic experimentson ligation of the coronary arteries, studied the cause

of the heart beat in mammals at the close of the 19thcentury and confirmed that Gaskell's observations on

the tortoise heart also applied to mammals.44In a comprehensive review of research on the origin

Vol. 76, No. 3, September 1987

of the heart beat published in 1900, Gaskell, in theopinion of physiologist and historian Chauncey Leake,unequivocally "established the validity of the myoge-nic theory of cardiac contractility."45 Gaskell summa-rized his contributions to the subject as well as thoseof other scientists and concluded that his explanationof 1883 "of the reason why different parts of the heartdiffer in rhythmical power-and explanation depend-ent upon the morphological differences of the musculartissue and not upon the presence or absence of ganglioncells-is right. Nothing that has since been written hastended to make me alter that opinion." He also reit-erated his belief that the sequence of contractions of thevarious parts of the heart was "not dependent upon thepresence of ganglion cells any more than the heart-beatitself."42

In Gaskell's words, "The fundamental experiment,and it is one of very great importance for all questionsconnected with the heart, is an experiment of the samecharacter as that originally performed by Romanes onthe muscular tissue of the Medusae; an experiment,namely, of cutting the muscular tissue of the heart, soas to leave only a small bridge of tissue over which thecontraction must pass, and then studying the block tothe passage of that contraction caused by reducing thisbridge more and more." Gaskell concluded, "Clearly,then, the natural pause between the contractions ofauricle and ventricle, can be explained without theintervention of any special nervous mechanism, ifthe contraction of the heart signifies the passage ofa contraction wave from one end of the heart to theother, over muscular tissue of varying power ofconductivity."42A major advance in our understanding of the origin

of the heart beat occurred in 1907 when Arthur Keithand Martin Flack published their classic observationson the sinus node. They wrote "Our search for a well-differentiated system of fibres within the sinus, whichmight serve as a basis for the inception of the cardiacrhythm, has led us to attach importance to this peculiarmusculature surrounding the artery at the sino-auricularjunction. In the human heart the fibres are striated,fusiform with well-marked elongated nuclei, plexiformin arrangement, and embedded in densely packed con-nective tissue." They concluded that it was within thisspecialized cardiac muscle "that the dominating rhythmof the heart normally begins."46

These studies finally provided a morphologic frame-work that made it possible to explain the physiologicphenomena that had been elucidated over the past cen-

tury. The weight of this additional evidence, togetherwith Gaskell's comprehensive and persuasive sum-

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mary of the myogenic theory published in 1900, essen-tially settled the long debate about the origin ofthe heartbeat.47 As Geison observed in 1978, Gaskell's "myo-genic theory and his concept of heart block were incor-porated into the pathology, pharmacology, and ther-apeutics of the heart, and his conclusions haveremained at the base of cardiology ever since."'3The classic observations of Foster, Romanes, and

Gaskell were the "stepping-stones," in Sherrington'sopinion, to the clinical work of James Mackenzie andThomas Lewis that established the scientific study ofcardiac arrhythmias in man. The electrocardiograph, ofcourse, was invaluable in identifying and classifyingabnormalities of impulse formation and conduction inman. The work of these men and their contemporarieswho established the "new cardiology" is beyond thescope of this review. A recent article by Lawrence 48outlines the early clinical applications of the scientificstudies that have been described here.

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W B FyeThe origin of the heart beat: a tale of frogs, jellyfish, and turtles.

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