Expériences doivent autant que possible être instituées sur des animaux inférieures.
Le plus faible le développement d’un organisme, le plus variété dans les unités plus petites, de sorte que, à un moment donné, elles vivre de façon autonome.
[Experiments must, whenever possible, be carried out on inferior animals. The simpler the development of an organism, the greater the variety within the smaller units, such that, at one moment, they can live in an autonomous way.]
—Claude Bernard, Cahier Rouge 
The relationship among cardiac pacemakers is characterized by the fact that one pacemaker is usually dominant and all the others are subsidiary. The sinoatrial node acts as the dominant pacemaker, and all other potential pacemaker tissues are discharged by a conducted impulse before their respective diastolic depolarizations attain threshold. These pacemakers are called subsidiary to emphasize the fact that, under normal circumstances, they are engaged in conducting impulses, but, under abnormal circumstances, they may become actual pacemakers.
In the mid-1800s, Hermann Friedrich Stannius placed a ligature between the sinus venosus and the auricle of a frog’s heart and reported a resultant standstill of the auricle and the ventricle. This finding was of great interest, for it was the first indication of the relationship between dominant and subsidiary pacemakers. The observation brought attention to not only the inhibitory action but also the actions of motor nerves to the heart, because the neurogenic versus myogenic origin of the heartbeat had still not been established. Some 30 years later, Walter Holbrook Gaskell approached the problem using a tortoise’s heart, at a time when evidence was accumulating for a myogenic rather than neurogenic cardiac impulse . My objective in this column is to review Stannius’s and Gaskell’s contributions, as they stand at the very foundation of our understanding of cardiac impulse conduction and the concept of block. Along the way, I provide some insights into their lives as well.
Hermann Friedrich Stannius (1808–1883)
Born in Hamburg, Germany, Stannius was an anatomist, physiologist, entomologist, and outstanding researcher. He attended elementary school in his native city until 1825, thereafter studying in the Gymnasium, proceeding then to Heidelberg and Breslau, where he received the medical doctor degree in November 1831 when only 23 years old. Stannius became an assistant physician at the Friedrichstadt Hospital in Berlin, at the same time establishing a medical practice and pursuing various scientific occupations that, in part, anticipated his later zoological works.
In Breslau, collaborating with Theodor Emil Schummel (1786–1848), a German entomologist who specialized in insects of the order Diptera, he produced a paper on entomology in 1832 and in 1836, in Berlin, a paper on the history of cholera up to the time of its devastating 1832 outbreak in France. Besides these, he translated from English a paper on pulmonary disease. He also published a text of general pathology in 1837 and translated a French text on skin diseases (1837–1839). In October 1837, he was appointed a full professor of medicine at the University of Rostock (in the German state of Mecklenburg-Vorpommern). This was the beginning of his most active research, which extended far beyond the circle of the then very small university.
The medical school there was very deficient and still in its rudimentary beginnings, with faculty members who were not particularly dedicated to research. Just before Stannius’s arrival, however, the energetic Karl Friedrich Strempel (1800–1872), an ophtalmologist and high school teacher who founded the Rostock University Clinic, had begun a push to change things there for the better. Stannius became the director of the newly established Institute for Comparative and Pathological Anatomy and Physiology; in addition, he initiated a comparative anatomy collection that grew rapidly, augmented not only by his colleagues but also by contributions from the numerous nearby boatmen fishing off the Baltic Sea coast who frequently brought him specimens, including valuable living snakes.
Stannius devoted most of his time to the anatomical examination of animals, their nervous systems, and the action of individual organs, such as the heart and the kidneys in healthy and diseased conditions; he also practiced vivisection. Thus, his institute soon gained widespread repute. Stannius, in this way, became one of the most prominent cofounders of modern medicine, even before Carl Ludwig –. For his animal investigations, the fish from the Baltic provided him with very rich material, which he partially described in a vertebrate anatomy textbook that appeared in Berlin in 1846. In fact, he authored many publications—the titles alone fill almost two pages in Blanck’s Mecklenburg physicians catalog—spanning 1832 to 1852, and he also published in outstanding journals, for example, Hufeland’s Journal of Practical Medicine and Müller’s Archiv für Anatomie. A number of important articles also appeared in Wagner’s Handbook of Physiology, the Berlin Encyclopedia of Medical Sciences, and Schmidt’s Encyklopädie der gesamten Medizin.
In addition to his scientific and scholarly activity, Stannius was a highly effective teacher, known for his clear lectures, penetrating observations, and overall knowledge. At the time, his experiments were relatively unorthodox, even startling in ways, and they often aroused strong opposition among the locals. He held several official positions, visiting Copenhagen in 1851 and Holland in 1857. Thereafter, he entered into a slowly developing depressive state. In 1862, he gave up his physiology lectures, and, in 1863, he left the institute altogether, as his depression and emotional imbalance increased. He spent the rest of his life (roughly 20 years) in the Irrenheil-Pflegeanstalt mental institution in the Saxon mountains near Schwerin. A sad, undeserved ending, indeed .
The Frog’s Heart Ligatures: Blocks
According to the Farlex Partner Medical Dictionary,
A ligature placed either around the junction between the sinus venosus and atrium of the frog or turtle heart (first Stannius ligature) or around the atrioventricular junction (second Stannius ligature) demonstrates that the cardiac impulse is conducted from sinus venosus to atria to ventricle, but that successive chambers possess automaticity since each may continue to beat, but the atria show a slower rate than the sinus venosus, while the ventricle either does not contract or beats at a rate slower than the atria.
In 1852, Stannius attempted such a procedure, which later became known as the Stannius I and Stannius II ligatures. His observations also indicated that the sinus is the pacemaker of the heartbeat . It is a rather long paper, not easy to follow and somewhat repetitive, the work having been carried out in several separate stages.
For example, Stannius placed ligatures on the two vagus nerves, finding no apparent heartbeat influence, and also on the venae cavae, observing that the heart continued its beating undisturbed. If the common venous sinus was tied off before its entrance into the atrium, contractions proceeded but no longer at the same frequency. The end result is summarized in the previous quotation from the Farlex dictionary.
There are several websites (and even YouTube videos) describing these experiments in detail. They can also be carried out on turtles and snakes [i.e., on herptiles (amphibians and reptiles)], which represent the many cold-blooded species with three well-marked heart stages, each showing electrical and mechanical activity. Related bibliographical material from the early 20th century comes from Erlanger , Erlanger and Hirschfelder , Hering , Cushny , and Conn and Lewis . These references provide a reasonably good idea of the knowledge about this subject half a century after Stannius’s 1852 paper.
In herptiles, the heart has three stages and four chambers: the sinus venosus, two atria, and one ventricle with its left and right side partially connected through the opening of an incomplete septum. There is some mixture of blood, but not too much, because of the particular helicoidal configuration of this wall. Each stage shows electrical activity and the associated mechanical contraction. Hence, blood moves from the sinus venosus to the atria to the ventricle.
In frogs, the sinus venosus has a triangular shape (Figure 1). It receives blood from the posterior vena cava, which brings it from the lower body, and from the right and left venae cavae, which return blood from the upper portion of the body. The pacemaker is usually at either the right or left side of the upper sinus venosus in the so-called presinus area. It is a natural oscillator with an unstable diastolic potential. From there, the electric impulse propagates to the other side and to the lower sinus venosus, then the atria, and then the ventricle. The snake is a good model for recording all cardiac events, electrical and mechanical (Figure 2). In 1969, I obtained a large collection of records demonstrating a variety of blocks, all taking place while the preparation slowly deteriorated. Some were elicited by vagal stimulation .
Walter Holbrook Gaskell (1847–1914)
The son of a barrister, Gaskell was born in Naples, where his family was spending the winter for the sake of his father’s health. He was educated at Highgate School and Trinity College, Cambridge, receiving his bachelor of arts degree in 1869 and becoming a fellow of Trinity Hall. He worked in the physiological laboratory of the University of Cambridge, focusing on the physiology of the heart and the vascular and nervous systems. Gaskell obtained his medical degree in 1878, although he never practiced professionally. In 1883, he became a university lecturer in physiology, a position he held until his death.
Gaskell received many honors during his career, including the positions of Croonian Lecturer and fellow of the Royal Society (both in 1882), the Royal Society’s Royal Medal in 1889, the Baly Medal of the Royal College of Physicians in 1895, and honorary doctoral degrees from Edinburgh and McGill Universities. His research included the sequence of cardiac contraction, dual autonomic control of the heart, introducing the concept of heart block, and experimental demonstration of the myogenic origin of the heartbeat. He also developed essential concepts for later understanding of cardiac arrhythmias.
Although he did not locate the precise origin of the sinus impulse, Gaskell’s landmark studies would become the basis for the 1907 anatomic discovery of the sinus node. His main contributions are those of 1882 (part of his Croonian Lecture)  as well as his 1900 publication regarding the contraction of cardiac muscle . Recent authors have focused attention on his scientific production as well as his life , . Throughout his life, Gaskell worked somewhat leisurely. From 1889 until his death, he pursued the evolutionary origin of vertebrates, unsuccessfully trying to prove that vertebrates originated from invertebrates. His final years were also saddened by his wife’s debilitating nervous illness, but he continued his work until the very end. Gaskell suffered a cerebral hemorrhage in 1914, dying at the age of 66.
Discussion and Conclusions
I have summarized Stannius’s and Gaskell’s experimental discoveries on heart conduction, trying to provide some of the many references available in the literature. In addition, brief biographical accounts of their respective lives were provided as examples for young researchers and medical students.
In his 1909 introduction to the inaugural issue of Heart, Gaskell wrote,
The experimental sciences of Physiology, Pathology, and Pharmacology are more and more directly influencing the study and practice of medicine. Slowly, but surely, the results of experiments gained in the laboratories are being applied to man. Medical study is losing its empiric character, and is founding itself on the well ascertained facts of Physiology and its cognate sciences, Pathology and Pharmacology.
Gaskell concluded that heart muscle itself possessed rhythmicity independent of the ganglia and that different areas were more rhythmical than others. He also observed that the dominant generator of the heartbeat (the tissue possessing the highest cardiac rhythmicity) was located in the sinus venosus, which beats spontaneously at the quickest rate, sending a wave of contraction over the rest of the heart at speeds that vary in different parts according to the nature of the muscular tissue. This knowledge turned out to be an essential basis for the work of James Mackenzie (1853–1925) and Karel Wenckebach (1864–1940), utilizing jugular and arterial pulse studies on patients at the end of the 19th century, and of Thomas Lewis, who applied Einthoven’s electrocardiogram (ECG) beginning in 1909. To summarize Gaskell,
- The power of independent rhythmical contraction decreases regularly as we pass from the sinus to the ventricle.
- The rhythmical power of each segment of the heart varies inversely as its distance from the sinus.
- The rhythmicity of the cardiac muscle varies inversely as its conductivity.
In 1907, Arthur Keith (1866–1955) and Martin Flack (1882–1931) were the first to discover the anatomic location of the sinoatrial node in the mammalian heart. Using the ECG, Thomas Lewis (1881–1945) in 1910 was able to show that the spread of excitation advanced throughout the heart. He verified that Keith and Flack’s sinus node was indeed responsible for the origin of the electrical impulse and that the electrical wave spread through defined conducting pathways. All this is another exciting piece of cardiology. In the years following Wenckebach’s and Luigi Luciani’s (1840–1919) elucidation of cardiac conduction blocks, two other papers appeared that deserve to be referenced , . From Stannius’s times until today, advances have been outstanding and dramatic, greatly improving clinical cardiology, with indubitably beneficial effects on extending lifespan. Research has played a significant role, and so we arrive at biomedical engineering as an integral part of the current medical profession .
A good point to recall in this brief overview is the sinus venosus of the snake (Figure 3), which can be seen in this photograph taken of a rather large Constrictor constrictor specimen (usually called the boa constrictor) that has had the organ clearly uncovered by blunt dissection; by turning it over, its right portion hangs out to the animal’s right side (in the supine position).
In summary, toads and frogs, snakes and serpents, turtles and terrapins, and caimans, alligators, and crocodiles (or, more succintly, the two classes of Amphibia and Reptilia, often named collectively Herptilia) do have sinus venosi showing minor differences. They are clearly structures similar to those in mammals, and their study has helped significantly in our understanding of mammalian heart conduction.
- C. Bernard, Cahier Rouge, translated by H. E. Hoff, L. Guillemin, and R. Guillemin. Cambridge, MA: Schenckman Publishing Co., 1967, p. 120.
- M. Vasalle. (1977). The relationship among cardiac pacemakers: Overdrive suppression. Circulation Res. [Online]. 41(3), pp. 269–277.
- M. E. Valentinuzzi, K. Beneke, and G. E. González, “Ludwig: The bioengineer,” IEEE Pulse, vol. 3, no. 4, pp. 68–78, 2012.
- M. E. Valentinuzzi, K. Beneke, and G. E. González, “Ludwig: The physiologist,” IEEE Pulse, vol. 3, no. 5, pp. 46–59, 2012.
- M. E. Valentinuzzi, K. Beneke, and G. E. González, “Ludwig: The teacher,” IEEE Pulse, vol. 3, no. 6, pp. 64–71, 2012.
- Deutsche Biographie. Stannius, Friedrich Hermann. [Online].
- H. E. Stannius, “Zwei Reihen physiologischer Versuche [Two series of physiological experiments],” Archive für Anatomie, Physiologie und wissenschaftliche Medizin, 1852, pp. 85–100.
- J. Erlanger, “On the physiology of heart-block in mammals, with especial reference to the causation of Stokes-Adams Disease,” J. Experimental Med., vol. 8, pp. 8–58, 1906.
- J. Erlanger and A. D. Hirschfelder, “Further studies on the physiology of heart-block in mammals,” Amer. J. Physiol., vol. 15, pp. 153–206, 1905/1906.
- H. E. Hering, “Über die wirksamkeit der accelerans auf die von den vorhofen abgetrennten kammern isolirten saugetierherzen [On the effectiveness of acceleration on the atria in separated chambers of the isolated mammalian heart],” Centralblatt Physiologie, vol. 17, no. 1, 1903.
- A. R. Cushny, “Stimulation of the isolated ventricle, with special reference to the development of spontaneous rhythm,” Heart, vol. 3, pp. 257–278, 1911/1912.
- A. E. Cohn and T. Lewis, “Auricular fibrillation and complete heart-block: Description of a case of Adams-Stokes syndrome, including the post-mortem examination,” Heart, vol. 4, pp. 15–31, 1912/1913.
- M. E. Valentinuzzi, “Electrophysiology and mechanics of the snake heart beat,” Ph.D. dissertation, Department of Physiology, Baylor College Med., Houston, TX, 1969.
- M. E. Valentinuzzi, H. E. Hoff, and L. A. Geddes, “Observations on the electrical activity of the snake heart,” J. Electrocardiol., vol. 2, no. 1, pp. 39–50.
- M. E. Valentinuzzi and H. E. Hoff, “Catheterization in the snake: Correlation of cardiac events,” Cardiovascular Res. Center Bull., vol. 8, no. 3, pp. 102–118.
- W. H. Gaskell, “Croonian Lecture: On the rhythm of the heart of the frog, and on the nature of the action of the vagus nerve,” Phil. Trans. Roy. Soc., vol. 173, pp. 993–1033, 1882.
- W. H. Gaskell, “The contraction of cardiac muscle,” in Textbook of Physiology, E. A. Schäfer, Ed. London: Young J. Pentland, 1900, pp. 169–227.
- M. E. Silverman and C. B. Upshaw, Jr. (2002, May 15). Walter Gaskell and the understanding of atrioventricular conduction and block. J. Amer. College Cardiol. [Online]. 39(10), pp. 1574–1580.
- M. E. Silverman and C. B. Upshaw, “Walter Holbrook Gaskell,” Clinical Cardiol., vol. 31, no. 7, pp. 340–341, 2008.
- M. E. Valentinuzzi, L. A. Geddes, and H. E. Hoff, “El fenómeno de Wenckebach-Luciani: Visión histórica [Wenckebach-Luciani’s phenomenon: Historical View],” La Semana Médica, Buenos Aires, Argentina (discontinued), vol. 138, no. 23, pp. 785–791, 1971. Also in Boletín Academia Nac Ciencias (Córdoba, Argentina), vol. 49, 2nd part, pp. 389–397, 1972.
- C. B. Upshaw, Jr., and M. E. Silverman, “Luigi Luciani and the earliest graphic demonstration of Wenckebach periodicity,” Circulation, vol. 102, pp. 2662– 2668, 2000.
- M. E. Valentinuzzi, Understanding the Human Machine: A Primer for Bioengineering. Singapore: World Scientific, 2004.