Ventricular Fibrillation Experimental Evidence and Basic Concepts 1880s1920s

It is generally accepted that the first experimentally induced fibrillation of the heart was the work of Carl Ludwig, then at the physiological laboratory of Zurich University, in 1850. During these years in Zurich Ludwig wrote the first volume of his famous Lerhbuch der Physiologie des Menschen, which treated diffusion and osmosis, acoustics and optics, hemodynamics and animal electricity, all topics of medical physics, which came to the fore through Ludwig's research. Apparently Ludwig became interested in application of du Bois-Reymond's newly devised electrophysiological methods to the animal heart. He and his collaborator Moritz Hoffa Ludwig demonstrated that a strong constant (faradic) current applied directly to the rabbit ventricle produced irregular and weak contractions, which they called Flimmern. Ludwig, however, did not continue his experiments on the electrical activity in the heart because the "fundamental action," he believed, could not be apprehended with the methods and instruments available.27

Although physiologists took the lead in studying electrical phenomena in living tissue, clinicians, interested in experimental research, too were keen in applying electricity as a therapeutic modality. The prestigious Prix Montyon of the French Academie des Sciences had a special category for the works in electrotherapy. Felix Edme Alfred Vulpian, professor of pathological anatomy at Paris University and staff physician at the Charite hospital, took a special interest in the action of the faradic current on the heart. A fine experimentalist, Vulpian showed that direct faradization applied directly to the ventricle of the dog heart caused irregular tremulous chaotic muscular movements of the ventricle, which he called mouvement fibrillaire, while the auricle continued to beat normally. Similarly, direct current applied to the auricle also led to fibrillary contractions, fremissement fibrillaire. Since Vulpian's experiment of 1874 the term fibrillation came into use to describe the phenomenon.28 Another eminent clinician at the Paris Faculte de Medecine, Germain See reported in 1879 that he induced ventricular fibrillation in the dog by occluding its coronary arteries.29

During that time, in the 1870s and 1880s, the controversy was ranging over the nature of cardiac automatism, whether the heartbeat was myogenic, that is, due to inherent excitation by the heart muscle itself, or neurogenic, that is, due to either neural or local ganglionic control. Since the discovery of the sympathetic and parasympathetic nerves and ganglia inside and outside the heart, and following the lead of Alfred Volkmann at Halle University, who suggested that the cardiac ganglia were the centers of automaticity, the neurogenic theory became ultimately dominant both in Germany and France. Studies on the effect of electrical stimulation of the nerves on the heart also provided convincing proofs of neurogenicity. Claude Bernard contributed, although indirectly, to the neurogenic theory through his demonstration of a reflex nervous mechanism in the endocardium and his "ganglionic" theory of vasomotor action. Alfred Vulpian, in his acceptance of neurogenic theory, depended heavily on the presumed analogy between cardiac inhibition and vasodilation.30 The leading center of the neurogenic view was Germany, since German physiological institutes led the field in general. Ludwig's institute, where important research on the innervation of the heart was pursued, became the major stronghold of neurogenicity. In Britain, Michael Foster was the major proponent of the myogenic theory. In fact, it was at his laboratory at Cambridge that Walter Gaskel performed experiments that appeared to definitively prove the myogenic theory. Before his work in Foster's laboratory, Gaskel had studied the innervation and vagal stimulation of the heart and the vasomotor control of blood flow in skeletal muscle arteries at Ludwig's laboratory. In Cambridge, Gaskel, working with an isolated strip of tortoise ventricular muscle devoid of ganglion and nervous connections, showed that the strip continued to pulsate at a rate similar to the intact heart. These experiments suggested to him that the rhythm of the heart beat depended on the persistence of a primitive condition of heart muscle but not on the presence of ganglion cells.31

Myogenic theory had its opponents, however, and they too had worked with Ludwig. Hugo Kronecker, Ludwig's collaborator for many years, and Ilia Cyon, with whom Ludwig discovered the depressor nerve, the vasodilator branch of the vagus nerve, back in 1866, were the most influential opponents among cardiovascular physiologists. Oskar Langendorff at the University of Konigsberg also preferred the neuroganglionar explanation over the myogenic hypothesis. Only a few German physiologists believed in myogenicity: Theodor Engelmann at Utrecht University studying cardiac automatism and conduction established it in the isolated ventricular beat. Wilhelm His, Jr., in Leipzig contributed fundamentally to extending Gaskel's results from the lower vertebrate to the mammalian heart. The most impressive claim of the myogenecists was the appearance of rhythmicity in the absence of differentiated nervous elements. But the neurogenesists had an equally strong argument, the obvious influence of nervous action on the intact heart beat.32

Most of experimentalists working with the mammalian heart were well familiar with ventricular fibrillation. It was generally treated as an experimental curiosity and definitive proof that atrial fibrillation, separate from ventricular fibrillation, was still lacking. Fibrillar contractions were referred to as delirium cordis. In 1899 Arthur Cushny clarified the terminology: in physiology delirium cordis referred to fibrillar contractions that arrest the circulation and prove rapidly fatal, whereas clinically, the term referred to extreme irregularity of the pulse.33

The first important research that treated VF with deeper insight into its pathophysiology was the work by John A. MacWilliam, a physiologist at Aberdeen University, who had, like every other physiologist, studied at Ludwig's laboratory. He was there at the same time as Walter Gaskel and Henry Bowditch of Harvard. In 1887-1889 MacWilliam published results of his experiments on ventricular fibrillation. He was convinced that the arrhythmia occurred independently of "any mechanical relation of the ventricles to the rest of the heart, and of any nervous relation of the ventricles to the rest of the heart or to the extra-cardiac nerves." He demonstrated that fibrillary movements of the heart were the result of the lack of harmony in the contraction and relaxation of the minute muscular fibers that compose the myocardium, thus supporting the myogenic character of VF.34 The general appearance of VF was well known, but MacWilliam's accurate and colorful description claimed both a new clinical significance for VF as a cause of sudden death, and its dependence on the changes within the "ventricular substance": "The cardiac pump is thrown out of gear, and the last of its vital energy is dissipated in the violent and prolonged turmoil of fruitless activity in the ventricular walls."35 In his review on electrical stimulation of the heart, MacWilliam differentiated cardiac arrest caused by asystole from that caused by VF. He suggested that fibrillation results from a rapid succession of uncoordinated peristaltic contractions, described the relationship of the refractory period to these changes, and presented evidence of the effect of certain poisons, which when injected into the blood stream, caused fibrillation of the ventricles.36

MacWilliam pointed out that although VF was known to be fatal in experimental animals, he sometimes managed to restore normal rhythm "by applying rhythmical compression of the ventricles with hand and administering pilocarpine intravenously."37 He referred to the previous investigation by the Berlin physician Hugo von Ziemssen on alterations in heart rhythm and rate induced by the application of electrical shock either directly to the heart open for surgery or through the thorax. MacWilliam's experiments also showed that electric shocks applied through a large pair of electrodes, one located on the ventricular apex and the other over the sixth or seventh dorsal vertebra, could be used to terminate VF in man. However, as MacWilliam pointed out, von Ziemssen's work of 1882 remained largely unnoticed, because the suggested technique was virtually impossible to use in the clinical setting.38 MacWilliam's ideas on cardiac resuscitation would only be appreciated and fully developed many years later by Carl Wiggers at the Western Reserve University.

Although MacWilliam's conception of the pathophysiology and clinical significance of VF was quite advanced, his work did not receive very much recognition during its publication.

Much later, in 1915 Lewis acknowledged that MacWilliam was the first to draw attention to the important fact that sudden death was often caused by VF.39

Several researchers around this time were attempting to study ventricular fibrillation in man using the new technique of electrocardiography. In 1911 Lewis and Levy used the electrocardiograph to demonstrate that when ventricular fibrillation occurred during chloroform anesthesia, it was often preceded by the appearance of multiform ventricular extrasystole or ventricular tachycardia.40 In 1912 Augustus Hoffmann published the elec-trocardiographic record of a patient with ventricular fibrillation, which occurred at the end of a period of paroxysmal ventricular tachycardia.41 The same year Canby Robinson of Washington University at St. Louis published electrocardiograms recorded from seven patients at the time of death, including two tracings, which were consistent with ventricular fibrillation.42 Explaining difficulties in documenting VF in humans Lewis wrote in 1915: "Remarkably, practically every form of irregularity, which has been produced experimentally in the mammalian heart, has now been recorded in clinical cases. But there is one notable exception Why is fibrillation of the ventricles so uncommon an experience? For a good reason: fibrillation of the ventricles is incompatible with existence. ...If it occurs in man it is responsible for unexpected and sudden death."43

With the understanding of AF as a uniquely atrial rhythm responsible for what was called arrhythmia perpetua, and the demonstration in the 1910s that it was distinct from VF, the question of the mechanism underlying fibrillation came into focus. Intensive studies on the experimentally induced fibrillation brought out several hypotheses. Hugo Kronecker argued that fibrillation resulted from the disturbance of a hypothetical cardiac "coordination center" regulated by nervous impulse; his experiments showed that a needle inserted into the upper third of the ventricular septum destroyed this center and induced VF.44 Surprisingly, Kronecker's hypothesis was not widely accepted, even though he was a greatly respected figure in the field of cardiac research, and many foreign physiologists studied at his institute in Bern. Kronecker and his students worked on problems concerned with virtually every area of cardiac physiology such as vascular innervation, cardiac poisons, irritability, and functional capacity of the heart. In 1895 Theodor Engelmann suggested that each heart fiber independently becomes rhythmical, and each is a focus of its own impulse formation due to increased excitability.45 Heinrich Winterberg further developed Engelmann's theory of multiple heterotopic centers in 1906.46 Lewis too supported the idea that activity from one or more heterogeneous centers may account for a single premature beat and for incoordinated activity during fibrillation.47 In 1915 the Viennese clinician Carl Rothberger and Winterberg proposed a contrasting theory of "tachysystole," which attributed fibrillation to extremely rapid discharge of a single focus, possibly due to vagal influence.48 In the 1920s these theories were replaced by the so-called circus movement theory, developed by the Cambridge physiologist George Ralph Mines49 and subsequently adopted by Lewis, who published a series of papers demonstrating the mechanism of circus movement in cases of AF and atrial flutter and their differentiation.50 Lewis based his idea of circus movement on the original studies on the umbrella of the jellyfish by the American zoologist Alfred Mayer. In 1906 Mayer demonstrated that a chemical or mechanical stimulus of the quiescent ring resulted in a band of contraction that went about the circuit in one direction for hours.51

There were two important contributors to the circus movement theory, George Mines and the American physiologist Walter Garrey. Assistant demonstrator at the Cambridge physiological laboratory, Mines was a fine and clever experimentalist. After visiting Marey's Institute in Paris in the early 1900s, where he saw Marey's invention, the first moving image camera, Mines used the novel method in his studies of cardiac contractions. While working at the Roscoff biological station in France, Mines became interested in developing Mayer's idea to explain the mechanism of fibrillatory contraction of the myocardial tissue. In 1913 Mines proved that "If a closed circuit of muscle is provided, of considerably greater length than the wave of excitation, it is possible to start a wave in this circuit that will continue to propagate itself round and round the circuit for an infinite number of times."49 Mines applied the idea of reentry to myocardial tissue and demonstrated it in his classical diagram showing normal tissue with rapid conduction and no reentry, and abnormal tissue with delayed conduction permitting reentry to occur. He formally pointed to the conditions necessary for reentry to occur: unidirectional block; recirculation of the impulse to its point of origin; and elimination of the rhythm by cutting the pathway.52 Interested in studying the onset of VF, Mines modified the technique by applying single shocks to the rabbit heart instead of the repeated electrical shocks as was usually done. By timing single shocks precisely at various periods during the cardiac cycle, he identified a narrow zone fixed within electrical diastole during which the heart was extremely vulnerable to fibrillation. Mines believed that stimuli, either external or from within the heart, could trigger fatal arrhythmia if the stimuli fell within this zone, and could cause death by disruption of what he called "dynamic equilibrium of the heart."53

Walter Garrey at Tulane University independently developed the circus movement theory and reentry mechanism as possible substrates for the generation of arrhythmias. He showed that when a fibrillating chamber was cut into four pieces, each fragment continued to fibrillate. He reasoned that the fragments were not dependent on a single tachysystolic center, the hypothesis proposed by Carl Rothberger. On the other hand, Garrey found that although portions of the isolated heart muscle were able to fibrillate, a critical amount of muscle mass was needed. He showed that a piece cut from any part of ventricular tissue obtained from mammals or turtles would cease fibrillating if its surface area was less than four square centimeters. These observations ultimately undermined the individual or multiple heterotopous centers theory. Moreover, if the ring was made thin enough, the uncoordinated fibrillatory contractions organized themselves into rotating waves that followed each other successively and repeatedly around the ring, in a manner similar to that described by Mines for circus movement reentry. Garrey provided the first mechanistic description of the arrhythmia as "intramuscular ringlike circuits," with resulting "circus contractions," which are fundamentally essential to the fibrillary process.54 He also pointed to the possibility of setting up vortex-like reentrant circuits around a stimulated region without any anatomical obstacle, an idea that was later dismissed by some theorists,55 but more recently confirmed by experimentalists.56

Although some continental physiologists, Carl Rothberger for example,57 were critical of the circus movement theory of fibrillation, this theory remained dominant for nearly 30 years, particularly in Britain. It had some very heavyweight supporters, such as Lewis. The theory was further developed to explain the complexity of experimental findings, including such concepts as a single "mother ring," which propagated the arrhythmia and generated "daughter rings," and multiple independent rings. Garrey, one of the early supporters of circular movement, argued in 1924 that the circuit, although present, could no longer be presented as a simple circuit due to blocks to its conduction: "[T]he impulse is diverted into different paths, weaving and inter-weaving through the tissue mass, crossing and recrossing old paths again to course over them or to stop short as it impinges on some barrier of refractory tissue."58

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