Cardio-Physiology Challenging Empirical Philosophy E-Book

Jochen Schaefer

• Herausgeber: Books on Demand
• Kategorie: Fachliteratur
• Sprache: Englisch

Seitenzahl: 495

Veröffentlichungsjahr: 2022

Beschreibung

With this volume of three essays, the authors want to create an opportunity for dialogue between different disciplines by taking a closer look at three cardio-physiological examples. In the essays presented, we will look at the exploration of different cardiological topics from the 20th century, all of which have contributed to a better understanding of certain aspects of cardiac activity. Not only do these insights provide a more complete picture of these cardiac phenomena, but it is also within this context that we can look for and into the patterns of regularities which govern this living organism. Our goal is to stimulate a dialogue on the philosophy of science in the spirit of Hans Reichenbach.

Leseprobe

Reha-Kliniken Küppelsmühle, Bad Orb1

These three essays are dedicated to the co-founders of the International Institute for Theoretical Cardiology Daniel Burkhoff, Michael R. Franz and David T. Yue as well as Ulrich Freund. It is also dedicated to the students of IIfTC, friends, and collaborators.

We remember with gratitude The Johns Hopkins School of Medicine, Baltimore, and its evolving Division of Cardiology in the 1960s under the guidance of Richard S. Ross.

1 Photo of the Reha-Klinken Küppelsmühle was kindly provided by Anne-Kathrin Dieulangard, Haitz-Gelnhausen // Cover Logo: International Institute for Theoretical Cardiology [IIfTC], https://www.iiftc.de

The authors

Brigitte Lohff, born 1945 in Hamburg, worked as a criminal psychologist in Hamburg after studying psychology; received her PhD in 1977 in history of science, biology and philosophy at Hamburg University and her habilitation in History of Medicine in 1986 at the Christian-Albrechts-University Kiel [CAU]. From 1994 until her retirement in 2013, she held the Chair of History of Medicine at the Medical School Hannover; visiting professorships at the universities in Vienna and Lucerne. Main research interests: Medicine and Public Health of the 19th and early 20th centuries, as well as the epistemology of medicine.

Jochen Schaefer, born 1930, studied medicine in Freiburg/Brsg. and doctorate in 1955; subsequently postdoc in pathology and pharmacology (FU Berlin).1960-1962 training at the evolving Division of Cardiology, Johns Hopkins Hospital, Baltimore, under Richard S. Ross; 1962 residency at I. Med. University Hospital, Kiel, to establish a division of modern cardiology; 1966 habilitation; 1970 Professor and Head of Special Cardiology at the CAU; 1985 leaving the service of the state of Schleswig-Holstein. 1981 to 1996 chief physician of the rehabilitation clinics-Küppelsmühle Bad Orb - Scientific interests: the interdisciplinarity of medicine and philosophy.

Johann P. Kuhtz-Buschbeck, born 1961, studied medicine from 1982 to 1989 in Kiel. He received his doctorate in the field of Pediatric Cardiology, where he worked as an assistant until 1991. Since then he has worked at the Institute of Physiology of CAU Kiel and as a postdoc guest researcher at the Karolinska Institute in Stockholm. His main research interest has been sensorimotor control (habilitation on locomotion in 2000), and he is also interested in the history of physiology.

Bernhard Thalheim, born 1952, studied mathematics at the TU Dresden. He received his PhD in discrete mathematics from the Lomonosov University, Moscow, in 1979. His habilitation followed in 1985 at the Technical University of Dresden. This was followed by professorships in Dresden Kuwait, Rostock and Cottbus before he took over the Chair of Information Systems Technology at CAU Kiel from 2003 to 2020. Visiting professorships led him for example to the University of Klagenfurt in Austria, to the Hungarian Academy of Sciences and to Massey University in New Zealand. His research area is the theory of conceptual modeling.

Ekkehart Rumberger, born 1939 in Chemnitz/Saxonia, received the PhD in Internal Medicine in 1971; 1977–2003 Professor and Director of the Department of Physiology at the Faculty of Medicine at the University Hamburg [Eppendorf]. Main research interests: The cardiovascular system and the Force-Interval Relationship (FIR). He retired in 2004.

TABLE of CONTENTS

Introductory remarks

1.1. The challenging of empirical philosophy by empirical physiology

1.2. The hiatus between research and epistemological classification of examples from cardio-physiology

1.3. Brief summary of the contents of the three essays

1.4. References

ESSAY I: The Physiological Function of the Force-Interval Relationship (FIR): A Forbidden Question?

Introduction

1.1. The historical background of the Force-Interval Relationship

1.2. Steps towards the exploration of the Force-Interval Relationship

1.3. Different explanatory models

The clinical relevance of the artificial stimulation of the heart

2.1. Are there metabolic and/or largely physiological limitations for the effectiveness of FIR?

2.2. Do cardiac output and blood pressure change under resting conditions and physical exertion during artificial heart stimulation?

2.3. What kind of relationship exists between the FIR and the Frank-Starling mechanism?

2.4. "The frequency stress test"

2.5. Influencing the force of contraction

2.6. Research into the interaction between cardiac activity and circulation

2.7. The recording of monophasic action potentials [MAP]

The negative staircase-phenomenon and its clinical relevance

The molecular lens: David T. Yue’s path from the macroscopic level of the FIR to the nano-level of e-c coupling

Hypotheses on the scientific theoretical classification of the FIR in heart mechanics

ANNEX: Publications of the Kiel-Hamburg Group 1970 to 2000

References

ESSAY II: From the Basic Insights and Description of Cardiac Mechanics to the Development of Cardiac Assist Systems

Introduction

1.1. Otto Frank and the physiological basics of heart activity

1.2 Otto Frank and the reception of his work in England

1.3. References

The scientific path of Jochen Schaefer and the beginning of cardiology as an independent discipline from the 1960s

2.1. The path to theoretical and clinical cardiology

2.2. The unknown Otto Frank in English-speaking countries

2.3. The development of modern cardiac surgery at the Johns Hopkins School of Medicine

2.4. References

Mechanical support for the insufficient heart: the development of cardiac assist systems

3.1. The arterial counter-pulsation

3.2. The intra-aortic balloon counter-pulsation (IABP)

3.3. Experimental studies on the cardiac dynamic effects of IABP

3.4. Controversies about the status of IABP and its clinical indication

3.5. Conclusions and derived options

3.6. Technical miniaturization of cardiac catheter systems and pumps

3.7. Clinical implications regarding an application of the Impella System

3.8. Digitalis glycosides for the treatment of heart failure

3.9. Early studies on cardiac oxygen consumption

3.10. ANNEX: Publications of the Kiel-Hamburg Research-Group 1965–1974

3.11. References

Review from today's perspective of physiology on concepts related to cardiac mechanics (Johann Kuhtz-Buschbeck)

4.1. Cardiac assist systems from a physiological perspective

4.2. Myocardial oxygen consumption and its estimation by appropriate indices

4.3. Pathophysiology and drug therapy of heart failure

4.4. References

Preliminary reflections on the models of the heart (Brigitte Lohff)

5.1. References

Model-Based Reasoning for Investigating the Heart Capability (Bernhard Thalheim)

6.1. Models and Modelling

6.2. Model-Based Perception, Imagination, and Reasoning

6.3. Model-Based Investigation

6.4. Final Remarks

6.5. References

ESSAY III: Laws of Circadianity and Cardio-physiological Rhythms: An Approach to Holistic Medicine?

Introduction

1.1. Setting the course

1.2. Traditional concept of spa town and the problem of proof of effectiveness

1.3. The concept of rhythmic functional order

Circadianity and its consequence for the diseased heart

2.1. Circadian oscillations of blood pressure

2.2. Circadian fluctuations of the heart rate

Chronobiological considerations in the context of spa medicine

3.1. Prevention, dietetics and sport

3.2. Chronobiology and sports

3.3. Integration of circadian rhythms in therapy and rehabilitation medicine

3.4. Considerations on the measurable effects of holistic medicine

Final consideration

4.1. Clocks are timekeepers about a permanently changing physical condition

4.2. The information quality of the data flow and periodic time sequences

ANNEX: Lectures and Publications on chronobiology from the IIfTC 1980 to 2020

References

PREFACE

The book we are now presenting, Cardio-physiology Challenging Empirical Philosophy, is published forty years after the founding symposium of the International Institute for Theoretical Cardiology in April 1982. Its cardio-physiological origins can be traced back to 1960. During these more than sixty years, many friends and scientists have actively accompanied its projects and, thus, contributed to interest-ing insights and suggestions, which have also become the subject of our essays. Given the complexity of the broad subject matter, we ask the reader to forgive occasional redundancies and repetitions.

We would like to thank them all for their contribution. In this acknowledgement, we want to make special mention of the participants at our Thursday Round Table, which has existed for more than twenty-five years, and their lively discussions between: Wolfgang Deppert, Anne-Kathrin Dieulangard, Hans-Carl Jongebloed, Claus Köhnlein, Björn Kralemann, Johann Kuhtz-Buschbeck, Claas Lattmann, Brigitte Lohff, Siegfried Munz, Klaus-Jürgen Nordmann, Brigitte Schaefer, Jochen Schaefer, Tim Schaefer, Bernhard Thalheim, Nicolaus Wilder.

The truly interdisciplinary diversity of opinions, views and works represented by them was and is an essential stimulant of the IIfTC.

1. Introductory remarks

With this volume of essays, we want to create an opportunity for dialogue between different disciplines by taking a closer look at three cardio-physiological examples. In the essays presented, we will look at the exploration of different cardiological topics from the 20th century, all of which have contributed to a better understanding of certain aspects of cardiac activity. Not only do these insights provide a more complete picture of the phenomena of cardiac activity, but it is also within this context that we can look for and into the patterns of regularities which govern living organisms. Our goal is to stimulate a dialogue on the philosophy of science in the spirit of Reichenbach. For Hans Reichenbach, as well as for László Kocsis and Adam Tamas Tuboly, the continuity between science and philosophy was bidirectional.2 Philosophy had to learn from the sciences and proceed from them, but still had its own role to play: "But a philosophy that draws its facts from science, that is able to shed light on the mysteries of scientific research and to clarify for the researcher, on the basis of his own achievements, the aims and methods of his work, can only be a welcome ally on the path to knowledge." 3

A few more reflections on the history of science introduce these essays to remind the reader that from the middle of the 19th century onwards, scientific experimentation became the guiding principle of medical biological research. The rapid increase in knowledge through experimentation required the integration of these new findings into necessarily changing views of what constitutes a healthy and sick human being.

1.1. The challenging of empirical philosophy by empirical physiology

It is an unwritten rule in biological-medical research that the question of what is the meaning of a physiological function should not be asked, rather only the "how" of the physiological mechanism should be answered. Since the middle of the 19th century, excluding the “why”-question was seen as a necessary prerequisite for expanding the stock of validated knowledge in physiology, which at that time was still in its infancy. As the field of physiology matured, a discussion was raised on how to make it comparable to the other natural sciences. Within this discussion, a critical debate was ignited surrounding the appropriateness of “how” vs. “why” questions within biomedical research. The physiologist and anatomist Johannes Müller (1801–1858), who became one of the most important teachers of physiologists from the middle of the 19th century, played a central role in this debate. His Handbuch der Physiologie des Menschen und der Thiere4 (Handbook of the Physiology of Man and Animals) and his reports on the progress of anatomy and physiology in Müller's Archiv der Physiologie und wissenschaftlichen Medizin5 became integral research-guiding writings for the anatomists, physiologists, and zoologists who followed him. As early as 1827, in his Grundriß der Vorlesungen über die Physiologie (Basic Lectures on Physiology), Müller formulated the claim that physiological research should be carried out according to scientific criteria to be recognized as natural science: "Such a work, if it is to be complete, [must] indicate the scope of this science in consistently equal and complete treatment and at the same time the achievements to date as well as those still possible and necessary to be demanded."6 However, research should not stop at the description of individual observations; rather it should place them in a superordinate context. In Müller's view, the recognition of the universal7 can only succeed if physiological and philosophical thinking is combined.8 To recognize a general principle or general rules from individual facts, Müller requires various categories of thought: "The teaching of physiology [...] cannot do without the logic of the essential or of speculation such as dialectics [...] And all material that has become empirically known can, if it is to be understood, be considered in that threefold way of thinking."9

A "logical connection of empirical facts" is not sufficient in and of itself, but „true physiology thinks life into right experience; through experience as well as through philosophical thinking, physiology comes about, to itself."10 [Only when] the different categories of thought mentioned above have been applied to all empirically known substances "does science come into being"11. This thought process was summarized by Müller in the guiding principle: "The physiologist experiences nature so that he thinks it."12 The classification of individual physiological phenomena into a concept of the "Aliveness of the organism" – i.e. in our terminology, the question of meaning – is necessary from Müller's point of view for the following reason: Speculative thinking allows us to understand the concepts or functions developed in reflection, in which "the becoming, the procedure of the general into the particular"13 contained therein are to be grasped.

Müller, however, thought that physiologists in his era still had to abstain from utilizing a speculative system on the 'physics of life': "Indeed, empirical physiology does not solve the final questions about life, but neither does philosophy solve them in such a way that we could make use of this solution in empirical science".14 Indeed, one cannot expect metaphysical theories from empirical science, but rather proof of whether a theory is true or false. But according to Müller, it does not make sense if the physiologist, out of "anxiety and caution", merely enumerates the facts rather than dare to say more about the knowledge gained."15 However, the classification into a superordinate system only makes sense if the assumptions contained therein agree with the empirical observations.16

Müller was a very influential scientist and built up an important school of anatomists and physiologists in the 19th century.17 The researchers of the following generation adhered to the demand to produce empirically proven facts, abstaining from interpretation and reflection on the question of how individual pieces of knowledge can be classified in a system of organic life. The overwhelming success of physiology from the 1840s onwards was continued by the prominent school of Carl Ludwig (1816–1895) in Vienna and Leipzig.18 Researchers from the second half of the 19th century concentrated their creative and systematic experiments primarily on the production of proven facts. This focus further relegated the classification of facts into a superordinate context of meaning into the background. The limitation of empirical and experimentally verifiable connections or mechanisms led to an explosive expansion of new insights into the biological processes of an organism. At the same time, this development was accompanied by an abundance of new measuring and recording methods that helped verify the knowledge gained through experiments.

This "quasi-ban" of examining the meaning or purpose of a physiological function continues to have an effect to this day. As it turns out, limiting physiological thought to the "how" question has proven to be successful. However, it seems to have been forgotten that Johannes Müller did not exclude the question of meaning, but rather had relegated it to the field of philosophical reflection. With the increasing number of individual observations, an epistemological discussion – as demanded by Ernst Cassirer (1874–1945) – was also lost in addressing this question to "transform the world of sensual impressions [...] first into a spiritual world, into a world of ideas and meanings."19

1.2. The hiatus between research and epistemological classification of examples from cardio-physiology

This “reluctance” to include “why” questions had consequences which prevented a dialogue to use insights gained from the natural sciences to create an epistemological classification. Classifying the biologic phenomena to understand the organic only occurred to a limited extent. The concepts presented by Hans Driesch (1847–1941), who dared to make this attempt with his Philosophy of the Organic in 1909, were widely refuted. Although he was recognized as an expert in developmental mechanics, but his concept of teleology for understanding and classifying observations in developmental biology received little recognition among biologists.20

This complex relationship between scientific research results and their epistemological classification can also be seen within research results from cardiac physiology. Hans Reichenbach’s introduction of the journal Erkenntnis in 1930 announced: "It has always been a program of the 'Annals' to pursue philosophy not as an isolated science, but in close connection with the individual specialist sciences [...]."21 However, this promise could only be fulfilled to a limited extent, at least for cardio-physiology. In the philosophy of science, the pumping function of the heart has been used repeatedly and rather superficially as an example of teleological thinking in science up to the present. The fundamentally new understanding of the physiology of heart mechanics in the 20th century has hardly been taken into account in epistemological analyses.22

Carl Gustav Hempel (1905–1997) demonstrates his concept of an explanatory model of the biological sciences using the phenomenon of a heartbeat:

"Historically speaking, functional analysis is a modification of teleological explanation, i.e., of explanation not by reference to causes which ‚bring about’ the event in question, but by reference to ends which determine its course. Intuitively, it seems quite plausible that a teleological approach might be required for an adequate understanding of purposive and other goal-directed behavior; and teleological explanation has always had its advocates in this context."23

Regarding the "function" of the heart, he states: "The heartbeat in vertebrates has the function of circulating blood through the organism."24 Hempel summarized his considerations in the following statement: "The heartbeat has the effect of circulating the blood, and this ensures the satisfaction of certain conditions (supply of nutrients and removal of waste) which are necessary for the proper working of the organism."25 Analytically speaking, his statement about the significance of the heartbeat is a summary of the "function of the heartbeat", which has been accepted in physiology since Harvey's theory of blood circulation in 1628. Through the causally based concept of blood circulation, the phenomenon of the pulse could be related to the contraction of the heart muscle. The idea that the blood serves to transport and distribute nutrients to maintain the viability of the organs has been accepted since the times of ancient doctors like Galen, even if the explanatory model of that time did not apply.26

Twelve years after Hempel's explanations, Ernest Nagel (1901–1985) also used the "blood pumping function" of the heart to illustrate the teleological explanation in science.27 This discussion continued within the philosophy of science. Ultimately, the term "function" was considered in its various semantic validations to determine its epistemological classification: "What is being asserted by this attribution of function? It might be held that all the information conveyed by a sentence such as can be expressed just as well by substituting the word 'effect' for the word 'function'. 28 In the philosophy of science literature, other words are used in addition to the term "function" in the same context as to why, how, goals, aims, purposes, mechanisms, teleology, teleonomy.29 Different positions have been taken as to whether biomedical scientists are obliged to use an epistemologically sound definition for their terms – in this context the term in question is "function". Ghiselin (2001) asserted his view for the contra-argument: "A stipulative re-definition of a term that we biologists routinely use to say what we mean can only lead to misunderstandings and confusion. Philosophers have no right to arrogate the role of determining how language shall be used in order to further their own metaphysical agendas."30

David Buller31 pointed out in 2002 that definitions of terms in the philosophy of science have developed primarily from the epistemological analysis of physics, which cannot simply be transferred to biology.32 It is inherent in biological manifestations that the principle of evolution, selection, and changeability in time is an indispensable part of the constitution of the living. Consequently, the teleological, as well as the historical, argument is inherent in the epistemological consideration of biological laws. "Buller's response is to note that any token of a trait has numerous effects, so one has to single out those which contribute to the fitness of the organism, and this can only be done historically. This looks to be an epistemological rather than definitional concern."33 When reviewing statements in the philosophy of science on the concept of function34 it becomes clear that the reference to the cardiovascular system served the authors for a certain type of scientific explanation. They ultimately did not push forward knowledge past the late 17th century. The question posed by Hempel: "What does the statement [the heartbeat has function of circulating the blood] mean,"35 has not been tested on other "functions" of the heart mechanics.

Using selected examples from cardio-physiology, we ask the question of whether the lack of a scientific-philosophical classification of experimentally and theoretically gained knowledge has consequences for the understanding of organic phenomena or, taking into account current cardio-physiological experience, can be a useful addition to both an empirical philosophy of science36 and cardio-physiology.

1.3. Brief summary of the contents of the three essays

The present first Essay on the history of the force-interval relationship (FIR) is the first in a three-part series. While performing our study on partial aspects of cardiac mechanics, stimulation and periodicity of cardiac activity we came to the following conclusion: Our aim was not only to trace the path of different discoveries of cardiac function, including J.S’s own research-history of the last 60 years, rather, we want to further explore the context of how progress was taking place. Using the discoveries in cardio-physiology, we have to ask ourselves the question of what practices were accepted and further pursued by the scientific community to gain insights into the special aspects of the cardiac function. We have asked ourselves e.g.: Why were at the same time some ideas and results "overlooked" as being of little interest? Why often decades passed until already existing concepts were taken up again? As a result, the original ideas were often forgotten, so that no reference was made to insights already gained and many things were "re-explored".

By exploring these three essays we want to illustrate the "jumps and turns"37 of progress and stimulate a scientific-philosophical discussion on current biomedical findings.

The second Essay is intended to describe the field of research in which physiologists have been working for over a hundred years to provide a complete description of the mechanical cardiac activity within the cardiovascular system. It began with Otto Frank's lecture in Munich "The work of the heart and its determination by the heart indicator" on Nov. 29, 1898: "The mechanical states into which the heart muscle enters would be fully described if we knew the tensions and lengths of the single elements at every moment of its activity."38

In the following 120 years there were extensive efforts – parallel to the development of new measuring methods – to elucidate the mechanics of the heart experimentally and mathematically. In the process of elucidating the mechanics we will take a closer look at Frank's students and scientists such as Hermann Straub, Kiichi Sagawa, Hiroyuki Suga and Daniel Burkhoff. They helped to create the mathematical and experimental conditions to gradually realize the goals Otto Frank had set for himself in 1898. Using Otto Frank's pressure-volume diagram, electronic and computerized models have been developed since the 1990s to determine their significance for cardiac mechanics even more precisely. These models led to the electronic HARVI-Simulation program, which was presented by Daniel Burkhoff in 2005 and has since been further developed, and which can be interpreted as a realization of Frank's visions. – In parallel with the HARVI Simulation program, it was possible to present a technology for cardiac-assist-systems/assisted circulation systems that can be successfully used to relieve both pressure and volume of the failing heart – which can hardly be influenced by medication.

The last field of research – which will be presented in the third Essay – is based on observations of the effects of rehabilitation medicine from cardiac patients. In the broadest sense, this is a future-oriented concept for implementing the importance of restricted heart rhythm variability (HRV) in the prognosis for individual patients with cardiovascular diseases. A prerequisite for such a concept is that one must first understand the phases of heartbeat and respiratory synchronization – which involves experimental mathematical modeling. The latest technical developments seem to confirm the ideas of Wolfgang Deppert, who in 2002 expressed the idea of a system time clock. With such a system it could be possible to determine the individual system times of a patient and then be able to classify them in their chronobiological pattern. In order to be able to develop such a concept, it is necessary to understand the phases of the synchronization of heartbeat and respiration – including experimental mathematical modelling. In this part we will present the different aspects from a historical and epistemology perspective of the cardiology, their theoretical concepts and experiments of the last 150 years.

1.4. References

Burkhoff, Daniel /Israel Mirsky/Hiroyuki Suga: Assessment of systolic and diastolic ventricular properties via pressure-volume analysis: a guide for clinical, translational, and basic researchers, in: Am J Physiol Heart Circ Physiol 289(2005):H501-H512, https://doi.org10.1152/ajpheart.00138.2005.

Buller, David J.: Function and Design Revisited, in: AriewAndrew /Robert Cummins/Mark Perlman (eds.): Functions: New Essays in the Philosophy of Psychology and Biology, Oxford 2002, pp. 225–243.

Cassirer, Ernst: Wesen und Wirken des Symbolbegriffs [1925], Darmstadt:Wissenschaftliche Buchgesellschaft 1994.

Frank, Otto: Die Arbeit des Herzens und ihre Bestimmung durch den Herzindicator (Vorgetragen am 29. November 1898) in: Sitzungsberichte Gesell. Morph. Physiol. München, 14(1898):147–156. Translation in: Kuhtz-Buschbeck, Rediscovery of Otto Frank's, 2018, Appendix A. Supplementary data, https://doi.org/10.1016/j.yjmcc.2018.04.017

Ghiselin M.T., Can biologists and philosophers see eye to eye in function, Hist. Phil. Life Sciences, 2001, pp. 279–284.

Hempel, Carl Gustav: Aspects of scientific explanation – Another essay in the philosophy of science, New York 1970.

Johansson, Ingvar/Niels Lynøe: Medicine & Philosophy – A Twenty-First Century Introduction, Frankfurt/Paris/Brunswik 2001.

Kocsis László /Adam Tamas Tuboly: The liberation of nature and knowledge: a case study on Hans Reichenbach’s naturalism, in: Synthese 199(2021):951–978, https://doi.org/10.1007/s11229-021-03224-2.

Lohff; Brigitte: Die Suche nach der Wissenschaftlichkeit der Medizin in der Zeit der Romantik. [Medizin in Geschichte und Kultur, 17], Stuttgart 1990.

Lohff, Brigitte: Facts and Philosophy in Neurophysiology. The 200th Anniversary of Johannes Müller (1801–1858), in: Journal History Neuroscience 10(2001): 277–292.

Lohff, Brigitte: Johannes Müller – Integration und Transformation naturphilosophischer Naturinterpretation, in: Olaf Breidbach/Thomas Bach (Hg.): Naturphilosophie nach Schelling, Frankfurt 2005, pp. 331–370.

Lohff, Brigitte: Die Josephs-Akademie im Wiener Josephinum. Die medizinischchirurgische Militärakademie im Spannungsfeld von Wissenschaft und Politik 1785–1874, Wien: Böhlau 2019, pp. 225–236, https://www.vr-elibrary.de/doi/pdf/10.7767/9783205232773.

Mac Donald, Graham: [Review] Andre Ariew/Robert Cummins/Mark Perlman (eds.): Functions: New Essays in the Philosophy of Psychology and Biology, in: Philosophical Reviews 2003.07.01, https://ndpr.nd.edu/news/functions-new-essays-in-philosophy-of-psychology-and-biology.

Müller, Johannes: Ueber das Bedürfniß der Physiologie nach einer philosophischen Naturbetrachtung (1824), in: Johannes Müller, Zur vergleichenden Physiologie des Gesichtssinnes des Menschen und der Thiere, Bonn: Cnoblauch 1826, S. 1–36.

Müller, Johannes: Grundriß der Vorlesungen über die Physiologie, Bonn: Cnoblauch 1827.

Müller, Johannes: Handbuch der Physiologie des Menschen und Thiere, Bd. 1, 2. Theil, Koblenz: Hölscher 1834.

Nagel, Ernest: Functional Explanations in Biology, in: The Journal of Philosophy 74, 5(1977): 280–301, https://doi.org/10.2307/2025746

Nagel, Ernest: Teleology revisited: Goal directed processes in biology, in: The Journal of Philosophy 74, 5(1977):261–279, https://www.jstor.org/stable/2025745.

Nagel, Goal directed processes in biology, 1977, p.263; Andre Ariew et al (eds.): Functions: New Essays 2002, p. 2; 157-171.

Reichenbach, Hans: The aims and methods of physical knowledge [1929], in: Marie Reichenbach/ R. S. Cohen (eds.): Selected writings 1909–1953, Vol. 2, Dordrecht: D. Reidel, 1978, pp. 118–166.

Reichenbach, Hans: Zur Einführung, in: Erkenntnis, 1(1930): I–V.

Schaffner, Kenneth F.: Theory structure, reduction, and disciplinary integration in biology, in: Biology and Philosophy, 8 (3) (1993): 319–347, https://doi.org/10.1007/BF00860432

Schröer, Heinz: Carl Ludwig, Begründer der messenden Experimentalphysiologie [Große Naturforscher, 33], Stuttgart 1967.

Wagenknecht, Susann/Nancy J. Nersessian/ Hanne Andersen (Eds.): Empirical Philosophy of Science-Introducing Qualitative Methods into Philosophy of Science, Heidelberg/New York 2015.

Weber, Marcel: Hans Drieschs Argumente für den Vitalismus, in: Philosophia Naturalis 36(1999): 263–293.

2 Kocsis/Tuboly, The liberation of nature and knowledge, 2021, pp. 951–978.

3 Reichenbach, The aims and methods of physical knowledge, in: Selected writings, 1978, p. 123.

4 The Handbuch der Physiologie was published in two volumes; the first volume from 1833–1844 in four revised editions, in each of which Müller incorporated current research.

5 Cf. Lohff, Facts and Philosophy in Neurophysiology, J. Hist. Neuroscience, 2001, 277–292 – Lohff, Integration und Transformation naturphilosophischer Naturinterpretation, 2005, pp. 331–370.

6 „Eine solche Arbeit, wenn sie Vollständiges leistet, [muss] den Umfang dieser Wissenschaft in durchgängig gleicher und vollständiger Bearbeitung und zugleich die bisherigen sowie die noch möglichen und notwendigen zu fordernden Leistungen bezeichnen.“ Müller, Grundriß der Vorlesungen über die Physiologie, 1827, p. I.

7 For the researchers of this time, the concept of the universal was associated with the question of how individual observations could be placed in the context of the meaning of living matter as opposed to dead matter.

8 „Jenes Allgemeine, welches nicht im Gegensatze ist mit dem Besonderen, sondern das Einzeln aus sich hervorbringt […], dieses ist das Prinzip der philosophischen Naturbetrachtung und dasjenige allein, was die Philosophie mit der Physiologie verbindet.“ ["The universal, which is not in opposition to the particular, but produces the individual from itself [...], this is the principle of philosophical observation of nature and that alone which connects philosophy with physiology."]. Müller, Ueber das Bedürfniß der Physiologie nach einer philosophischen Naturbetrachtung, 1824, p. 7.

9 Die Lehre der Physiologie […] kann der Logik des Wesenhaften oder der Speculation wie der Dialektik nicht entbehren […] Und aller empirisch bekannt gewordener Stoff läßt sich, wenn er begriffen werden soll, in jener dreifachen Weise des Denkens betrachten.“ Müller, Grundriß, 1827, p. V.

10 „die wahre Physiologie denkt das Leben in die richtige Erfahrung; durch die Erfahrung sowohl als durch das philosophische Denken kommt die Physiologie zustande, zu sich selbst.“ Müller, Von dem Bedürfniß, 1824, p. 37.

11 Müller, Grundriß, 1827, p. IV.

12 „Der Physiolog erfährt die Natur, damit er sie denkt.“ Müller, Von dem Bedürfniß, 1824, p. 34.

13 „das Werden, Procediren des Allgemeinen zum Besonderen“ Müller, Grundriß, 1827, p. 76.

14 „Es ist wahr, die empirische Physiologie löst die letzten Fragen über das Leben nicht, aber die Philosophie löst sie auch nicht auf eine solche Art, dass wir von dieser Lösung in einer Erfahrungswissenschaft Gebrauch machen könnten,“ Johannes Müller, Handbuch der Physiologie, Bd. 1, Theil 2; 1834, p. VI.

15 Müller, Handbuch, Bd. 1, 1834, p. VII.

16 Müller, Handbuch, Bd. 1, 1834, p. VII.

17 Among Müller‘s students were, for example: Hermann von Helmholtz, Emil Du-Bois-Reymond, Ernst Brücke, Theodor Schwann, Jacob Henle and Rudolf Virchow.

18 Cf. Schröer, Carl Ludwig, Begründer der messenden Experimentalphysiologie, 1967 – Lohff, Die Josephs-Akademie, 2019, p. 225-236. In France Claude Bernard plays a comparably central role in the implementation of modern physiology.

19 „die Welt der sinnlichen Eindrücke […], erst zu einer geistigen Welt, zu einer Welt der Vorstellungen und Bedeutungen umzuschaffen“ Ernst Cassirer, Wesen und Wirken des Symbolbegriffs, [1925], p. 99.

20 Cf. Weber, Drieschs Vitalismus, Philosophia Naturalis, 1999, 263–293.

21 Reichenbach, Zur Einführung, Erkenntnis, 1930, p. I.

22 Nagel, Teleology revisited, Journal of Philosophy, 1977, 261–279.

23 Hempel, Aspects of scientific explanation, 1970, p. 304.

24 Ibid., p. 305

25 Ibid

26 Cf. to the history of the cardiovascular system, Johansson/ Lynøe, Medicine & Philosophy, 2001, 33–39; 142–151.

27 Nagel, Functional Explanations in Biology, Journal of Philosophy, 1977, 283–286.

28 Hempel, Scientific explanation, 1970, p.305.

29 In this list the term "biological law" is missing, although biologists use this term to describe the consistent observation of regularly occurring and predictable biological phenomena. Examples for the use of the term law are: "Starling’s Law of the heart"; "Frank’s Law of the heart"; "Kleiber’s Law."

30 Ghiselin, Can biologists and philosophers see eye to eye in function, Hist. Phil. Life Sciences, 2001, p. 280.

31 Buller, Function and Design Revisited, 2002, 225–243.

32 For the complex issue of the structure of biological theories, cf. Schaffner, Theory structure, reduction, and disciplinary integration in biology, Biology and Philosophie 1993.

33 Cf. MacDonald, [Review] Andre Ariew et al., Functions, Philosophical Review, 2003, 07.01.

34 Cf. Nagel, Goal directed processes in biology, 1977, p.263 – Ariew et al (eds.): Functions: New Essays 2002, p. 2; 157–171.

35 Hempel, Scientific explanation, 1965, p. 305.

36 Cf. Wagenknecht et al., Empirical Philosophy of Science 2015.

37 The aphorism "jumps and turns" is used for the multiple changes of direction of an animal that crosses the original track or returns to it.

38 Frank, Die Arbeit des Herzens,1898, p.147.

CARDIO-PHYSIOLOGY CHALLENGING EMPIRICAL PHILOSOPHY

ESSAY I

The Physiological Function of the Force-Interval Relationship: A Forbidden Question?

Brigitte Lohff / Jochen Schaefer In cooperation with Johann P. Kuhtz-Buschbeck and Ekkehart Rumberger

TABLE of CONTENTS

Introduction

1.1. The historical background of the Force-Interval Relationship

1.2. Steps towards the exploration of the Force-Interval Relationship

1.3. Different explanatory models

The clinical relevance of artificial stimulation of the heart

2.1. Are there metabolic and/or largely physiological limitations for the effectiveness of the FIR?

2.2. Do cardiac output and blood pressure change under resting conditions and physical exertion during artificial heart stimulation?

2.3. What kind of relationship exists between FIR and the Frank-Starling mechanism?

2.4. "The frequency stress test"

2.5. Influencing the force of contraction

2.6. Research into the interaction between cardiac activity and circulation

2.7. The recording of monophasic action potentials [MAP]

The negative staircase-phenomenon and its clinical relevance

The molecular lens: David T. Yue’s path from the macroscopic level of the FIR to the nano-level of e-c coupling

Hypotheses on the scientific theoretical classification of the FIR in heart mechanics

ANNEX: Publications of the Kiel-Hamburg Group 1970 – 2000

References

Cover picture: Scheme of the Heart ©B. Lohff/ Fig. from: J. Schaefer: Darstellung des Aortendrucks, 1971, p. 357 (Permission to reprint by Springer Nature)

1. Introduction

In 1983, Arnold M. Katz wrote a historical review of the 30-year development of research into the Regulation of Myocardial Contractility from the perspective of a "brief and personal history.” Katz paraphrased this history of research with a playful yet apt metaphorical subtitle, calling it “An Odyssey”.39 Jochen Schaefer has been working on the force-interval relationship of the heart [FIR] in clinical research since the 1960s, both theoretically and practically. As a member of a research group of cardio-physiologists, he has also experienced an odyssey in the elucidation of the function of the FIR and has personally helped to shape it. The following paper uses a historical perspective to trace the development of hypotheses, experiments, and knowledge on the role of the FIR in cardiac mechanics. The written sources of the last 60 years of research on FIR will be underpinned and supplemented, taking into account the personal perspective on this history of research.

1.1. The historical background of the Force-Interval Relationship

The dependence of the force development of a heart muscle on the (preceding) stimulus interval (i.e., the frequency) during electrostimulation – later known as the staircase phenomenon – was first described in 1871 by Carl Ludwig's American student Henry Pickering Bowditch (1840–1911)42 at the Leipzig Physiological Laboratory.43 The following experimental observation was thus described - as summarized by Schütz in 1958:

"He [Bowditch] observed that the first amplitude of contractions after a longer resting period was lower than the amplitudes of the contractions registered before the period of rest. The contractions following the first beat gradually increased in amplitude again. This staircase phenomenon occurs especially after prolonged cardiac arrest."44

Bowditch had already suspected a far-reaching significance of the staircase phenomenon for the understanding of heart mechanics: "The interval between a contraction of the heart and the pre-ceding beat is of such importance for the strength of the contraction that a study of these effects a prime necessity."45 Bowditch's observation was never followed up on though in either Ludwig's laboratory or any other research group. Only 30 years later, in 1902, Robert Session Woodworth (1869-1956) developed his staircase concept based on Bowditch's work.46 He verified this phenomenon experimentally and provided an initial physiological explanation for this effect:

"The length of the optimum interval is governed by the interplay of two opposing factors, […] No long series of rapid beats is necessary to produce an increase in height. A single contraction following another at a short interval is sufficient to increase the height of the following contractions. The shorter also the interval between two contractions, the greater is their strengthening effect on the following contractions. [...] The two opposing factors are then the stimulating effect of a rapid succession of contractions, and the recuperative effect of a long pause. On the one hand, the following of one contraction close upon another acts to accelerate the production of available energy immediately afterwards; but on the other hand, the production of available energy is a gradual process, and a long pause enables more to accumulate than does a short pause. A short interval preceding a contraction tends to make that contraction weak and the following contractions strong."47

In the following six decades of the 20th century, roughly 200 publications that dealt with the force-interval relationship appeared, however, they mainly considered changes due to chemical and physical influences.48 The significance of this phenomenon was interpreted by Schütz in 1958 as follows:

"Thus, the staircase phenomenon reveals the relationship between two basic biological states: rest and activity. In other words, the staircase creates a condition favorable to activity, which deteriorates during inactivity, and vice versa, inactivity and rest create a favorable intracellular milieu for themselves and stabilise themselves by making it more difficult for the activity to develop again."49

The characteristic features of the course of the "staircase phenomenon" (“Treppe-Phänomen”) in the isolated heart muscle was already presented in a diagram by Woodworth in 1902.50

1.2. Steps towards the exploration of the Force-Interval Relationship

From the mid-1960s onwards, new - also clinically relevant - possibilities for artificial heart stimulation developed utilizing pacemaker technology. In this context, several research groups were formed internationally - including in Kiel and Hamburg - to study the theoretical and clinical aspects of artificial heart stimulation (electro-stimulation). At that time, physiologists in general had different approaches for investigating physiological problems, which were also used in FIR research. The respective experiments in the research context of the stair phenomenon led to partly contradictory results. In 1963, the research situation could be characterized as follows:

"Nevertheless, much confusion remains regarding the processes underlying the interval-strength relationship and their interaction. Apparent conflicts have arisen because of attempts to generalize from observations made on a single species or on muscle from a single region of the heart. Seemingly contradictory results have been obtained under experimental conditions that differed with respect to temperature, ionic environment, oxygen supply, and other factors."51

Further confusion in the investigation on “the staircase effect” resulted from the terminology used to describe this phenomenon:

"The terminology has become increasingly confusing: basic processes have been referred to by terms that describe only one of their manifestations and in some cases several manifestations of the same process have been described as independent entities. Some of the terms that have been used suggest knowledge of the changes in the myocardium which are responsible for the interval-strength relationship […]."52

At the same time, the in-situ and in-vivo experiments led to results that were not identical: "although all theories concerning the nature of these changes are highly speculative."53

Hans Reichel came to a similar conclusion in 1960 in his account of muscle physiology: "A theory of stairs seems premature as long as the individual conditions of the formation of the staircase have not yet been sufficiently studied."54 These statements indicate the complexity of the research that the scientists faced. Since the 1960s, it has been accepted within cardiological research that the staircase effect is a basal property of the heart muscle cell. In 1961, Vladislav Kruta and Pavel Braveny studied Woodworth's work and explained the possible function/significance of the stimulation interval for the process of heart contraction:

"The fact, that the activation, besides triggering the contractile mechanism, modifies at the same time the rate of contractility restitution, and with it the strength of contraction according to the length of the preceding interval, may be of definite physiological significance in a muscle adapted to rhythmical activity. It leads to the idea of self-regulation in the heart muscle, of an efficacious mechanism – and perhaps the only possible one – allowing for a gradation of mechanical response in rhythmical activity."55

In 1963 Koch-Weser/Blinks essentially followed Woodworth's interpretation of the phenomenon of 1902 and concretized it accordingly:

"Each time heart muscle is excited, two temporary changes in the muscle result that have opposing effects upon the degree of activation of the contractile elements in subsequent beats. One change tends to decrease contractility; it is responsible for the negative inotropic effect of stimulation (NIEA). The other tends to increase the strength of subsequent contractions and is manifest as the positive inotropic effect of activation (PIEA)."56

They expanded their interpretation when they spoke of "propagated action potential" and thus referred to electromechanical coupling as the basis for triggering a heart contraction:

"In mammalian heart muscle both changes result whenever there is a propagated action potential, whatever the interval preceding it, and whatever the strength of the resting contraction. Both changes disappear with time, and both are capable of cumulation. The cumulation of each depends on the amount of change produced per beat, on the interval between beats, and on the characteristics of the disappearance of the change with time."57

In 1963 there were no theory-based statements about the material basis of the negative inotropic effect of activation (NIEA) and the positive inotropic effect of activation (PIEA), rather there were only descriptions of observations:

"Until the nature of the factors responsible for the interval-strength relationship [FIR] has been determined, it will be possible to detect changes in them only through their effect upon contractility. In other words, the effect on contractile strength of interval-dependent changes in the muscle must be used as an index of the intensity of these changes."58

The hypothetical assumptions of PIEA and NIEA inspired different research groups to clarify the underlying mechanisms. Thus, researchers from Kiel and Hamburg also began to work on this topic in the mid-1960s. From the beginning, this group took an interdisciplinary approach, with the consequence that the clarification of these phenomena required a broad theoretical, methodological, and clinical research approach. Thus, physiological, statistical-mathematical, myocardial mechanics, pharmacological, pharmacodynamic, and clinical approaches were taken to address these questions. At the end of the 1970s, this interdisciplinary research concept was intensified through international cooperation with scientists in London and Baltimore, USA. Subsequently, this led to an extension of the theory of FIR. A decisive step forward was taken with the work of David T. Yue and Daniel Burkhoff when they extended the concept of PIEA and NIEA with the theory of intracellular calcium stores in 1982.59 Yue illustrated the hypothesis of mechanical coupling [e-c coupling] in a graphical representation.

Fig. 1: Hypothetical scheme of the e-c coupling, Yue 198660

At the end of the 1980s, the following reliable findings existed:

"It is generally accepted that the rise of intracellular free Ca2+ concentration after an electrical stimulus determines the tension development of heart muscle. […] Several models of cellular ca2+ transport have been developed to describe the force-interval relationship in mammalian muscle. The general hypothesis is that the action potential triggers Ca2+ release from an intracellular compartment into the sarcoplasm. This activator Ca2+ induces force production by the contractile filaments. An uptake compartment sequesters a fraction of the activator Ca2+ and the Ca2+ that enters the cell during the action potential. Transport of Ca2+ from the uptake to the release compartment is assumed to occur with a time constant of - 1°s."61

Chronologically summarized, in the following years until 2000, further aspects were examined to further clarify the FIR phenomenon:

Areas of research relating to FIR 1980 – 2000

The extension

62

of the measurement technique for the derivation of action potentials

63

in the isolated muscle cell using the patch-clamp method

64

The derivation of monophasic action potentials from the heart in situ

65

The development of the concept of calcium-antagonists

66

The physiological relevance of calcium

67

The development of variable stimulation methods

68

and their effect on the heart muscle mechanics

69

1.3. Different explanatory models

Koch-Weser/Blinks systematized the research results on FIR in their 50-page review in 1963 to make the different results on FIR recognizable. Major differences in the development of force to the FIR were documented:

"If experimental conditions are constant, the variations in the interval-strength relationship of muscle taken from the same region of the heart of individuals of the same species are relatively slight. On the other hand, differences among various types of heart muscle are pronounced, and it is impossible to consider the interval-strength relationship in any comprehensive way without referring to them."70

The FIR is influenced by several factors:

"In ventricular muscle from most mammalian species, increases in frequency over a wide range, lead to a greater additional cumulation of the PlEA [positive inotropic

effect of activation] than of the NIEA [negative inotropic effect of activation]. In the cat papillary muscle, the rested-state contraction is usually weak […]. Rarely its strength may be considerable, and then slight decreases in the strength of contraction occur with increases of frequency in the long-interval range. In guinea pig and rabbit ventricles the strength of contraction is greater at low than at intermediate frequencies."71

The observations are interpreted by Koch-Weser/Blinks as follows:

"It seems likely that in the ventricles of most mammals the degree of activation increases with frequency up to the maximum rate that the ventricle can follow. If this is true, the strength of contraction also will increase with increasing frequency until the duration of the active state shortens the direction of the change."72

The summarized results clearly illustrate that the researchers were confronted with numerous "contradictions" during the experimental investigation of the FIR. To understand the importance of the FIR for cardiac mechanics in all its complexity interpreting these “contradictions” was necessary. This meant an analysis of methodical, experimental, and species-specific differences and then taking them into account in the evaluation.

Differences in the expression of the FIR were found concerning 1) species, 2) cold-and warm-blooded animals, 3) experimental conditions, 4) varying influences of active substances.

ad 1) Conspicuous differences of the FIR were observed in the rat heart compared to other mammalian hearts, which resulted from a variety of experimental arrangements and were irritating:

"The interval-strength relationship of rat-myocardium is atypical but not fundamentally different from that of other species […] the relationship is similar in atrium and ventricle […]. As in cat atrium, the rested-state contraction is strong […] and the strength of contraction decreases as frequency is raised; however, the decrease continues beyond the frequency at which the cumulation of the PIEA becomes predominant in other species […]. Only at very high frequencies does the increase in the strength of contraction occur, and then it is often small […]. This has been attributed to a lack of, potentiation ‘in this species. Actually, much of the PIEA cumulates at higher frequencies in rat myocardium, as is evidenced by […] and post-extrasystolic potentiation […] in this species. Because the cumulation of the NIEA is very marked […], rest potentiation is particularly prominent in rat myocardium […]. The marked cumulation of the NIEA prevents the cumulation of the PIEA from becoming manifest in the interval-force curve until high frequencies are reached."73

They interpreted the results as follows:

"It seems likely that in most preparations of isolated rat heart muscle the full manifestation of the change responsible for the PIEA is prevented at high frequencies (400–500/min) by an inadequate oxygen supply to the central fibers. These frequencies are normal for the rat heart, and it would be surprising if rat heart muscle contracted very weakly at physiological frequencies. This question could be settled by studying the interval-strength relationship in blood-perfused rat hearts."74

ad 2) Rumberger and Reichel observed that the effects of an artificially induced frequency increase in a cold- or warm-blooded animals differ significantly. In 1972 they offered the following explanation for this difference:

"Whereas in the guinea pig’s papillary muscle the amplitude of optimal test contraction increases with the frequency of foregoing stimuli, the amplitude is depressed in the cold-blooded preparations by a rise of frequency. This effect is found to be due to the shortening of the action potential. Thus, the mechanical response of cold-blooded preparations seems to depend primarily on the duration of depolarization under different conditions of stimulation. In the guinea pig’s papillary muscle, the same changes in the time course of depolarization can be observed, but their effect on the contractile force cannot be revealed in such experiments. A much more predominant role in the force development of a papillary muscle may be attributed to the immediate influence of frequency on the contractile mechanism, i.e., to the pure frequency potentiation which does not exist in the myocardium of cold-blooded animals. These differences may be explained by the different development of Ca++ stores of the sarcoplasmic reticulum in heart muscle of cold-and warm-blooded animals."75

Ad 3) Already in 1982, Wohlfart and various co-authors had devoted themselves to studying the relationships between stimulus intervals of different lengths, action potential duration, and maximum force developed.76 Lewartowski and Pytkowski established that the mechanism of FIR is different from post-extrasystolic potentiation.77

Ad 4) At the beginning of the 1960s, the influence of pharmaceuticals and active substances on the FIR had been experimentally proven:

"Perhaps the most important of these factors is the time interval between contractions. Changes in the frequency of contraction may cause large quantitative changes in the effects of drugs on the strength of contraction of heart muscle, and may even reverse the direction of the effect. Drugs having similar effects on the strength of contraction at one frequency may have quite different effects at another. Analysis of the relationship between drug action and the frequency of contraction has already provided a means of distinguishing several different types of inotropic action, and may well lead to a better understanding of the mechanisms through which drugs change myocardial contractility."78

In addition to the aforementioned differences, the researchers faced another difficulty in classifying their observations correctly. They also found differences in the expression of the FIR effect within a species, depending on whether the experiments were conducted under in-situ or in-vitro conditions: The FIR is more pronounced under in vitro conditions than in situ. In 1976, Reichel described the effects of the isolation of the heart from the body on intracellular processes:

"Denervation deprives the heart of its normal adrenergic and cholinergic control via the sympathetic and parasympathetic pathways. In a heart which is blood supplied by a donor animal of the same species, normal contractility is maintained, probably by blood borne catecholamines or possibly by unknown inotropic agents of the donor. A heart receiving blood oxygenated by isolated lungs is in a state of failure. Substitution of blood by a cell and protein free solution diminishes oxygen availability in cardiac muscle, both in the perfused and bathed preparation. In the un-physiological environment, myocardial cells lose K+ and gain Na +. Under best possible conditions of oxygen supply but in a later stage of perfusion, contractility during rhythmical stimulation is depressed more at lower than at higher rates. Frequency potentiation and the inotropic effectiveness of noradrenaline are more pronounced in vitro than in situ. In excised papillary muscles and ventricular and atrial strips, the disarrangement and a more or less severe lesion of individual fibers accelerate the decay in mechanical performance."79

Reichel concluded his considerations with the remark: "The role of endogenous catecholamines for the maintenance of normal contractility in situ and in vitro is still a matter of discussion."80 This fundamental problem existing within experimental biomedical research had already been addressed at the beginning of the 19th century.81

Ignaz Döllinger (1770–1841), professor of physiology in Würzburg and Munich, stated in 1824 that there was a relevant difference between the physiological functions observed in the intact organism and those determined by experiment: "Despite all the valuable advantages of opening up living animals, some very strange phenomena remain in the ecology of the entire organism, about which these experiments provide no information."82 Döllinger considered whether experiments on isolated organic structures could not lead to results which only allow statements about a "pathological state" of the organism. Despite "enrichment through the experiment", restrictions are to be taken into account, because "the animal subjected to the tortures [comes] through the experiment itself into conditions that do not occur in the undisturbed progress of life."83

With the observed differences regarding the FIR under experimental conditions invitro and in-situ, the following should also be taken into account: Under in-vitro conditions, individual heart muscle cells or cells in the tissue are stimulated and the response to the stimulus is measured under constant conditions.84 In in-situ observation, the entire heart (as well as the vascular system) reacts under the influence and effect of nervous, hormonal, hemodynamic conditions, etc. Thus, the response to a stimulus sequence to trigger the FIR is at the same time overlaid by other "lawlike" conditions of the heart contraction. In the in-situ examination it must be taken into account, for example, that the FIR is influenced by the Frank-Starling mechanism (pressure-volume diagram)85, as well as the fact that "the warm-blooded heart [...] is full of norepinephrine and adrenaline stores, which also release their active substances and influence the heart muscle when electrically stimulated."86

To minimize the influence of the Frank-Starling mechanism on the FIR, pacing protocols using temporary cardiac pacemakers had to be developed and examined. This clinically relevant question prompted the "test interval" methodology for the first time. This methodology is based on the fact that, at different stimulation frequencies, a stimulation pause of equal length is switched on and the contraction force is measured. The representation derived from these measurement results gives the "pure force-frequency relationship". This concept, presented by the Kiel-Hamburg Group in 1971, made it possible to quantitatively record the contraction force generated by the interval-force relationship even under clinical conditions:87

Fig. 2: Graphical representation of the effect of stimulus intervals of different lengths on the force-frequency relationship, Rumberger/Reichel 197288

2. The clinical relevance of the artificial stimulation of the heart

With the knowledge that medication alone would be an inadequate treatment for many temporary or permanent disturbances of the rhythm of the heartbeat, the 1960s’ clinical cardiologists developed the idea of using an artificial electrical stimulation of the heart to bridge a rhythm disturbance, either temporarily or permanently. This therapeutic option was further advanced by rapid technical developments in the field of pacemaker systems. The Kiel-Hamburg Group was amongst one of the groups who was focussing their research on the following issues: When it came to applying artificial stimulation to the heart, the challenge was dealing with two different approaches: on the one hand, there is the theoretical-experimental model of the force-interval relationship [FIR] and its physiological or pathophysiological significance, and on the other hand, there is the clinical, application-oriented influence of pacemaker technology on the heart rhythm. Jeffrey pointed out in 2001 exactly how bold this idea was at the time:

"Why should any reader who is not a cardiologist wish to know about the pacemaker and the ICD? Certainly, mechanical technologies are more accessible to the non-expert, but there is something breath-taking about the audacious idea of taking over from nature the management of the human heartbeat and the ensuing quest to design electronic devices that would emulate nature ever more perfectly."89

The phenomenon of electro-mechanical coupling (excitation-contraction coupling) marked the starting point and physiological basis for solving this clinical application with the use of a pacemaker.90 In several steps, the Kiel-Hamburg group explored how the basics of the FIR phenomenon are related to the therapeutic application possibilities with the pacemaker and how the resulting clinical implications can be implemented with clinical electrostimulation. In the following, this process will be illustrated by the research questions of this group. Due to the abundance of related theoretical and clinically relevant topics, we will limit ourselves to some of the problems that had to be solved as a matter of priority at that time and the approaches derived from them.

2.1. Are there metabolic and/or largely physiological limitations for the effectiveness of FIR?

Monroe and French could prove through their experiments in 1961 that at different stimulation frequencies (30, 122, 182 and 254 Hz):

"… at any given volume, the ventricle was capable of a higher peak systolic pressure at a higher heart rate, demonstrating the treppe-phenomenon.91 […] The treppe-phenomenon was demonstrated in that increases in rate were accompanied by increases in systolic pressure. The oxygen consumed per minute by the isovolumetrieally beating heart invariably increased with an increase in heart rate. In those experiments in which the treppe effect was substantial, the oxygen consumed per beat likewise increased with an increase in heart rate."92

It had been proven that the stair phenomenon (positive staircase) could be observed as long as sufficient energy (oxygen) is available. "It is unlikely that oxygen lack ever limits the contractility of the normal heart muscle in situ at any frequency of contraction. In blood-perfused dog ventricle the strength of contraction has been reported to increase with all increases of frequency examined."93 The staircase phenomenon is thus one of the "basic laws" in biology, such as Kleiber's law for the relationship between mass and metabolism94 or laws regarding the cardiovascular system in different animal species95 and the optimization of the construction plan of the animals.96

2.2. Do cardiac output and blood pressure change under resting conditions and physical exertion during artificial heart stimulation?

Preliminary work by Kumada et al (1967)97 and Ross et al (1965)98