7333.». :BY? Michigan State University {H 2:113 This is to certifg that the thesis entitled MYOCARDIAL CONTRACTILE FORCE MONITORED BY STRAIN GAGE TRANSDUCERS ON THE INTACT DOG HEART presented by William E. Elzinga has been accepted towards fulfillment of the requirements for fl degree in My Major professflr (1 Date Februar 22 1967 4d 0-169 ABSTRACT MYOCARDIAL CONTRACTILE FORCE AS MONITORED BY STRAIN GAGE TRANSDUCERS ON THE INTACT DOG HEART by William E. Elzinga The output of blood from the heart is directly dependent upon myocardial force and/or velocity of contraction. The first derivatives of cardiac force and Ventricular pressure (indirectly) should quantify this "contractile velocity" of the myocardium. This study was designed to investigate the first derivative of cardiac contractile force (df/dt) as an index of heart performance; further, to investigate the rela— tionship between maximal df/dt and maximal dp/dt (the first derivative of pressure). To monitor cardiac contractile force, a tension transducer (gage) was constructed. The transducer consists of two strain gages (each 350 ohms) attached by epoxy resin copper beryllium shim stock (6mm x 14mm). The transducer was then encapsulated (in silastic sheeting) to reduce tissue reaction. The shim (and thus the transducer) was arched to approximate the curvature of the heart. To study heart muscle tension, the strain gage transducer (S.G.T.) was sutured firmly to the epicardium. The ability of the S.G.T. to sense changes in heart performance was tested (3 dogs). The S.G.T. was energized by and its output recorded by a Grass Model 5 polygraph. In addition, to facilitate data analysis, on some occasions gage output was stored on magnetic tape William E. Elzinga (Sanborn Model 2000) from which signals could be displayed subsequently upon a Tektronix Model 564 dual beam storage oscillos00pe. Differentiation was done electronically. When myocardial contractility was increased (epinephrine), the transducer registered an increased contractile force (after 2.5 ug epinephrine, cardiac force increased from 9.8 gm to 21.2 gm tension). Occlusion of large vessels (venae cavae, descending and ascending aorta and pulmonary artery) near the heart also were used to vary cardiac performance. Again, the S.G.T. detected the altered myocardial contractility. These results suggest that the tension transducer is capable of detecting variations in cardiac contractility in the intact‘ dog. The gage data correlate highly with intracardiac pres— sure data (r = .7 to .9). The first derivative of cardiac contractile force (df/dt) was found (18 dogs) to quantify the heart’s ability to alter readily its velocity of contraction. The results show that (l) chloroform . . . hinders, (2) epinephrine facilitates and (3) ouabain slowly potentiates the ability of the myocardium to alter cardiac contractile force and thus the intraventricular blood pressure. A high degree of correspondence (r = .6 to .9) between dp/dt and df/dt was found throughout the investigation. This suggests that df/dt and dp/dt are actually measuring similar aspects of myocardial performance: the rate function of tension build—up in cardiac muscle. The high degree of correlation between the two means of estimating cardiac MYOCARDIAL CONTRACTILE FORCE AS MONITORED BY STRAIN GAGE TRANSDUCERS ON THE INTACT DOG HEART .1‘ By *5. I’M a ‘a’ 5. ’J‘ William E? Elzinga A THESIS Submitted to Michigan State University in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY Department of Physiology 1967 ACKNOWLEDGMENTS The author expresses his sincere appreciation to Dr. W. D. Collings, Professor of Physiology, Michigan State University, for his interest, encouragement and coordination of his Ph.D. program. The writer also expresses his gratitude to the members of the guidance committee, Dr. W. L. Frantz, Dr. P. O. Fromm, Dr. E. P. Reineke, and Dr. D. A. Reinke for their teaching, interest and suggestions during the course of his program and especially to Dr. D. A. Reinke for taking extra time to provide instruction in the technique of transducer fabrication. The author is also indebted to Mr. K. R. Irish who kindly constructed and advised in the electrical equipment necessary for the completion of the problem. ii TABLE OF CONTENTS Page ACKNOWLEDGMENTS . . . . . . . . . . . . . ii LIST OF TABLES . . . . . . . . . . . . . vi LIST OF FIGURES . . . . . . . . . . . . . viii LIST OF APPENDICES . . . . . . . . . . . . xi Chapter I. INTRODUCTION 1 II. SURVEY OF LITERATURE A Muscle Mechanics . . . . . . . A Thermal Aspects of Muscle Contraction . . A Functional Anatomy and Movements of the Heart . . . . . . . . . . . . l2 Anatomy . . l2 Movements of the Heart During Contraction . 1A Application of Skeletal Muscle Mechanics to Heart Muscle . . . . . . . . . . l7 Force-Velocity Relationships of Skeletal and Heart Muscle . . . . . . . . l7 Myocardial Contractility . . . . . . . 19 The Need for a Definition of Terms . . . 19 A Useful Definition of Myocardial Con- tractility . 20 Myocardial Contractility as Defined by Changesixithe First Derivative of Ventricular Pressure Pulse . . . . . 21 Measurements of Cardiac Performance by Strain Gage Transducers . . . . . . . . . 25 Types of Strain Gage Transducers . . . . 25 iii Chapter III. IV. Potential Limitations of the Strain Gage Transducers . . . Characteristic Investigations with the Strain Gage Transducer . . CHANGES IN CARDIAC CONTRACTILE FORCE AND Page 27 28 INTRAVENTRICULAR BLOOD PRESSURE IN RESPONSE TO EPINEPHRINE AND VESSEL OCCLUSION Purpose of Investigation . . . . . Materials and Methods . . . Experimental Animals Surgical Techniques Instrumentation . . . Results 0 o o o o o o‘ o 0 Force and Pressure Response to Epinephrine Force and Pressure Response to "Venous Occlusion” . . . . . . . . Force and Pressure Response to Occlusion of the Descending Aorta . . . . . Force and Pressure Response to Occlusion of the Ascending Aorta . . . . . Force and Pressure Response to Occlusion of the Pulmonary Artery . . Discussion and Conclusions A COMPARISON OF THE RATE OF CHANGE (FIRST DERIVATIVES) IN CARDIAC CONTRACTILE FORCE AND INTRAVENTRICULAR BLOOD PRESSURE WHEN ALTERED BY CHLOROFORM, EPINEPHRINE AND OUABAIN . . . . . . . . . Introduction and Purpose . Importance of the First Derivative of Intraventricular Blood Pressure Pulse . Historical Aspects of the Use of the First Derivative, A Qualitative Approach Quantitative Analysis of the First Derivative of Pressure Pulse . . . Relationship of Myocardial Contractile Activity and the First Derivative of Pressure . iv 30 30 31 31 31 31 32 32 35 A8 A9 52 57 61 61 61 62 63 65 Page Chapter Materials and Methods . . . . . . . . 67 Experimental Animals . . . . . . . 67 Surgical Techniques . . . . . . . . 67 Data Collection . . . . . . . . . 67 Results . . . . . . . . . . . . 69 Effects of Chloroform Inhalation on Cardiac Force and Pressure . . . . . . . 69 Effects of Epinephrine on Cardiac Force and Pressure , , , . , . . . . 76 Effects of Ouabain on Cardiac Force and Pressure . . . . . . . . . . . 87 Discussion and Conclusions . . . . . . 9A BIBLIOGRAPHY 108 APPENDICES 118 Table 10. 11. LIST OF TABLES Page Effects of epinephrine on right cardiac contractile force and intraventricular blood pressure . . . . . . . . . . . . . AA Occlusion of large veins to heart: effects upon right cardiac contractile force and intraventricular blood pressure . . . . . A8 Occlusion of descending aorta: effects upon right cardiac contractile force and intra— ventricular blood pressure . . . . . . . A9 Occlusion of ascending aorta: effects upon right cardiac contractile force and intra— ventricular blood pressure . . . . . . . 52 Occlusion of pulmonary artery: effects upon right cardiac contractile force and intra— ventricular blood pressure . . . . . . . 57 Effects of chloroform inhalation on the maximal rate of force rise and maximal rate of pressure rise . . . . . . . . . . . . . . 1A2 Effects of chloroform inhalation on the time integral of right ventricular contractile force and pressure . . . . . . . . . . . 143 Effects of chloroform inhalation on the duration of the time interval for cardiac force and pressure 1AA Effects of chloroform inhalation on force and pressure at the maximum derivatives . . . . 145 Effects of epinephrine on the maximal rate of pressure rise and the maximal rate of force rise . . . 1A6 Effects of epinephrine on the duration of the time interval of cardiac force and pressure . 1A7 Effects of epinephrine on the time integral of pressure and force measurements . . . . . 1A8 vi Table 13. IA. 15. 16. 17. Page Effects of epinephrine on the force at maximal rate of force rise and pressure at maximal rate of pressure rise . . . . . . 149 Effects of ouabain on the maximal rate of pressure rise and the maximal rate of force rise . . . . . . . . . . . . . . 150 Effects of ouabain on the duration of the time interval of cardiac force and pressure . . . 151 Effects of ouabain on the time integral of pressure and force measurements . . . . . 152 Effects of ouabain on cardiac force at maximal rate of force rise and the pressure at maximal rate of pressure rise . . . . . . . . 153 vii Figure IO. LIST OF FIGURES Page Effects of 2.5 ug epinephrine upon carotid and ventricular blood pressure and right cardiac contractile force . . . . . . . . 3A Comparison of changes in right cardiac force and ventricular blood pressure in response to 2.5 ug epinephrine . . . . . . . . . . 37 Effects of 5.0 ug epinephrine upon carotid and ventricular blood pressure and right cardiac contractile force . . . . . . . . . . 39 Comparison of changes in right cardiac force and ventricular blood pressure in response to 5.0 ug epinephrine . . . . Al Response of blood pressure and right cardiac contractile force to occlusion of superior and inferior venae cavae and azygos veins . . . . A3 Response of blood pressure and right cardiac contractile force to occlusion of the descending aorta (midthoracic region) . . . . . . . A7 Response of blood pressure and right cardiac contractile force to occlusion of the ascending aorta . . . . . . . . . . . . . . 51 Response of blood pressure and right cardiac contractile force in response to occlusion of the pulmonary artery . . . . . . . . . . . 5Al Comparison of force displacement transducer (F.D.T.) and strain gage transducer (S.G.T.) when sutured on the surface of frog gastrocnemius muscles 56 A.——Diagram showing the technique of calibrating the strain gage transducer. B.-—The experimental determination of the rela- tionship between the Grass pen deflection and the force (from S.G.T.) expressed in grams . . 71 viii Figure ll. 12. 13. 1A. 15. 16. 17. Page A scheme of data collection and analysis system . . . . . . . . . . . 73 A.--A scheme showing the relationship between aortic blood pressure, right ventricular blodd pressure and its derivative (dp/dt) for a complete cardiac cycle. B.——A scheme showing the relationship between aortic blood pressure, right ventricular contractile force, and its derivative (df/dt) for a complete cardiac cycle . . . . . 75 A.—-Typica1 changes in right cardiac and ventricular pressure in response to chloroform inhalation. B.--Changes in right cardiac force and ventri- cular pressure in response to chloroform inhalation for all dogs . . . . . . . . 78 A.—-Right contractile force response to chloroform: cardiac force. B.--Response of right ventricular pressure to 0.7 mg ouabain: ventricular pressure . . . 80 A.—-Typica1 changes in right cardiac force and ventricular pressure in response to 2.5 ug epinephrine. B.--Changes in right cardiac force and ventri— cular pressure parameters in response to 5.0, 2.5 and 1.25 ug epinephrine 82 A.—-Oscillosc0pe trace illustrating the effects of epinephrine on myocardial contractility. B.——Oscilloscope trace of an increase in myocar- dial contractility as shown by an increase in intraventriular pressure and its first derivative (dp/dt) . . . A.--Changes in the duration of the "time interval" in response to 10.0, 5.0, 2.5, and 1.25 ug epinephrine. B.—-Scattergram of changes in the "time interval” in response to epinephrine 8A 86 ix Figure Page 18. Typical changes in right cardiac contractile force in response to 0.7 mg ouabain . . . . 89 19. A.——Changes in right cardiac contractile force in response to 0.A mg ouabain B.—-Typical changes in right intraventricular blood pressure in response to 0.7 mg ouabain . 91 20. Oscilloscope trace illustrating the effects of ouabain on contractility . . . . . . . 93 21. A scheme showing the first derivative of cardiac contractile force when all fibers in the heart contract simultaneously . . . . 100 22. A.--Changes in right cardiac contractile force in response to 2.5 ug epinephrine, closed chest unanesthetized dog. B.——Changes in right cardiac contractile force in response to 2.5 ug epinephrine, open chest, anesthetized dog. C.-—Changes in heart rhythm: closed, chest unanesthetized dog, in supine and standing positions . . . . . . . . . . . . 105 23. The wheatstone bridge in which each strain gage transducer forms l/A of the bridge . . . . 13“ 2A. Circuitry for coupling the strain gage trans- ducer to the grass amphifiers . . . . . . 137 25. Circuitry of the electrical differentiator . 139 LIST OF APPENDICES Appendix Page A. STEPWISE CONSTRUCTION OF STRAIN GAGE TRANSDUCER USED TO MEASURE THE MYOCARDIAL CONTRACTILE FORCE . . . . . . . . . 119 B. LIST OF MATERIALS . . . . . . . . . 125 C. CHRONIC EXPERIMENT . . . . . . . . 129 D. STATISTICAL FORMULAE . . . . . . . . 1A0 xi CHAPTER I INTRODUCTION The study of muscle physiology has occurred in two separate directions, the molecular and mechanical. The former is concerned with protein structure and chemical reactions of muscle (60). The latter approach seeks to describe the physical performance of muscle fibers. The investigation of the structural changes in muscle during contraction has taken place to a large extent with the electron microscope. It has been demon- strated that the smallest unit of a muscle fibril is composed of proteins, actin and myosin, and muscle shortening results when these two proteins in some way slide together (81). The chemical process underlying this movement is unknown. However, the energy source is adenosine triphosphate (61). The chemical nature of muscular contraction has been investigated indirectly. These studies have utilized metabolic and thermal techniques, whereby the oxygen uptake and/or heat liberated by the tissue reflects the energy used in chemical reactions of shortening. The mechanical properties of muscles have been studied under a variety of different conditions (66). Great strides have been made in the understanding of skeletal muscle performance. Recently, that which is known about skeletal muscles has been applied to cardiac muscle mechanics 1 and in many instances, this approach has given a better understanding of cardiac contractility (82, 8A). There are essentially two ways to study muscle mechanics. First, by directly measuring the force generated by the muscle and/or the rate at which the fibers shorten, and secondly, by indirectly measuring changes in the object or substance that the muscle has acted upon. For example, skeletal muscles move appendages and cardiac muscles move blood. Cardiac performance is usually investigated by considering the heart either as a pump which is made of muscle or as a muscle which is acting as a pump. .Some scientists are concerned mainly with how much blood the heart is capable of pumping and express their results in terms of cardiac output or stroke volume. Still others are concerned with how the heart, as a muscle, can vary its output of blood. Numerous researchers have studied the heart as a muscle. It has been demonstrated that the myocardium can increase its force and velocity of contraction (86). By increasing its force,the myocardium provides a higher systolic intraventricular blood pressure; by increasing its velocity,the ejection of blood from the ventricle occurs more rapidly. This investigation is a study of these two properties, force and velocity, of the myocardium. Its purpose is to describe in detail the manner in which the cardiac contractile force and the velocity of contraction change in relation to variations in the intraventricular blood pressure. Chloroform, epinephrine and ouabain were used to alter the contractility of the heart in order to provide changes in force and pressure measurements. For direct measurement of cardiac contractile force, a specially designed strain gage transducer was constructed. The transducer was sutured firmly to the epicardium of the heart. The ability of the transducer to measure changes in cardiac contractile force was investigated. CHAPTER II SURVEY OF LITERATURE Muscle Mechanics Thermal Aspects of Muscle Contraction Much was already known about the concept of energy when studies of muscle physiology were only beginning. The laws of thermodynamics were well established by this time. It was known that transformations of energy are associated with the liberation of heat and that chemical compounds probably contain energy which is used for many biological phenomena. It was most likely then, because so much was known about energy, that the first studies on muscles were thermal. It was hOped that such thermodynamic studies would provide useful clues to the intimate mechanisms involved in muscle contraction and would give some insight to the relation of the mechanical event and chemical changes. Strictly from a historical stand-point, it is of interest that the earliest work done on muscle heat pro— duction dates back to Heidenhain in 186A. He discovered that if weights were hung on a muscle (not after-loaded) that the heat production, caused by the contraction of the muscle and the lifting of the weight, increased with increasing weights. In 1878 Fick supplied evidence that the contraction heat also increased with increasing load even if the muscle always contracted from the same initial A position. It was further demonstrated by Blix in 1901 that a muscle gives off more heat in an isometric contrac— tion than in an isotonic one. Many of the modern heat production studies were by A. V. Hill and Hartree (57). One of the major problems confronting them, and one which confronts scientists today, was the construction of an apparatus which would give highly accurate readings of temperature changes occurring in the contracting muscle. Hill, after many years of experimentation with thermocouple,perfected a highly sensitive galvanometer which was quite satisfactory. Muscle contraction is accompanied by the liberation of heat under aerobic conditions in two principal phases, the initial and delayed heats (37). The maximal initial heat production lasts for a very short time andeas described by Hill as being instantaneous (36, 38). The maximal delayed heat phase occurs after the mechanical event is over and lasts for a longer time. The delayed heat is at least as great as the total heat liberated during the contraction (initial heat). Hill explained that initial heat production was associated with the energy used in actual muscle contraction, i.e., the shortening of fibers in isotonic contraction or build-up of tension in isometric contraction. He suggested that delayed heat was the restoration of initial heat. It was later shown (39), that if heat measurements were carried out in nitrogen, in place of oxygen, only an initial burst of energy was released. This indicates, as pointed out by Hill, that energy required for contraction of muscle is derived from nonoxidative reactions. The restoration of this energy, on the other hand, depends exclusively on oxidative processes. This was the first recording of the phenomenon Of oxygen debt. The time course of heat production in contracting muscles was well defined by Hill's early experiments (37, Al). The second step in the study of muscle mechanics was the search for factors that caused the initial heat produc— tion to vary. Fenn‘s investigations of the relationship between work performed and energy released (2A, 28), opened this so called ”second stage." He found that the amount of actual energy liberated by a muscle is not constant for any given initial condition of the muscle but varies with the load. A large load resulted in the liberation of more energy than a small load. This concept came to be known as the ”Fenn Effect,” which states that the muscle in some way can adjust its output of energy to the task required of it. The discovery that heat production in contracting muscle depends largely on the conditions to which it is subjected led to investigation of the effect of varying the muscle length on the amount of heat produced during an isometric contraction. It was found (3A) that if a muscle is allowed to shorten before or during the develOpment of tension, the heat production may be 20 to 30 percent smaller than it would have been had the muscle never been allowed to shorten. If, however, the muscle is allowed to shorten only when the tension has already reached its maximum value, then the heat production is in no way affected by the shortening. This led Hill to suggest that after the tension is maximal, the muscle acts as a purely elastic body with potential energy capable of doing work or of being liberated in the form of heat. From results of the previous study,Hill (38) proposed a theory to explain events that occur in a muscle contraction. He states that in an isometric contraction a "damped element" (contractile element) shortens and stretches an elastic element. In this way the overall length of the isometrically contracting muscle does not change. The tension generated by the muscle reflects the recoil prOperties of the elastic elements. Hill suggests that the contractile elements in a muscle develop a maximal "active state" or force almost instantaneously. The "active state” is associated with the initial stage of heat production. The contractile elements deliver a certain quantity of energy for a finite period of time and immediately thereafter relaxation takes place. During the ”active state” of the contractile elements, the elastic elements are being stretched and tension (force) of the muscle builds up in direct prOportion to the degree of stretch. The total force that a muscle can develOp depends to a large extent on the duration of the fully "active state" of the contractile elements. If the contractile elements remain in the fully "active state" for a longer period of time (during repetitive stimulation),more of the available energy would be used and more stretching of the elastic elements would occur giving a greater tension developed by the muscle. For example, during a tetanic muscle contraction, the developed force is greater than that which occurs for a single muscle twitch. The above theory was tested by changing a muscle length physically before and during a muscle twitch (31). By stretching a muscle at various intervals after stimu- lation,it should be possible to prestretch the elastic elements and the contractile elements then should deveIOp a greater force than if no prestretching had occurred. That is, the total force developed by the muscle should be equal to the physically prestretched elastic elements plus the force developed by the contractile element. Gasser and Hill (31) discovered that the sooner the muscle is stretched after it is stimulated, the greater the developed force. It was concluded that the contractile elements develop their full force (fully ”active state") almost instantaneously after the stimulus is applied. The prestretching in succeeding intervals after the stimulus, gives a smaller force because some of the energy is already dissipated in stretching the elastic elements prior to the prestretching. From the results of the previous study, Gasser and Hill (31) formulated a definition of the ”active state" of muscle contraction as follows: The stimulus is followed by a wave of depolarization followed within some mill-seconds by a sudden decrease in extensibility of the muscle, a decrease of extensibility that is pre— sumable the mechanical sign of a vigorous shortening of the contractile elements; this change which is called the development of the ”active state" lasts for only a short time during which the elastic elements are stretched. Associated with the "active state" of muscle contraction which characterized the initial phases of contraction, it was also found desirable to find some expression that would cover all phases of the isometric contraction. This expression was determined by Hill (AA) to be the ”tension-time" measurement, or the total areander the tracing of an isometric contraction curve. The total area was found to be directly proportional to the total energy used in the contraction (A2). Hill used the ”tension-time" index because during isometric contraction of muscles no external work is done. However physiologically, work is being done to promote the internal ”shortening" and to maintain a tension. In isometric contractions the extra rate of energy turnover is directly proportional to the tension developed. Muscles demand an increased rate of 10 energy consumption proportional to the tension developed even if no external work is done. Perhaps the most striking discovery by A. V. Hill is that muscle heat production is a simple linear function of the degree of fiber shortening (39, A6). When a muscle was allowed to shorten at variable velocities, the force and heat production diminished considerably as the speed of shortening increased. The faster an active muscle shortens, the further the tension fell or as the speed of shortening of the muscle increased, the work done (or the tension developed) fell off linearly according to the \ equation W = WO — kV, where W is the work done, WO the potential energy, K a constant and V the velocity of contraction (A3). Since the inverse "force-velocity” or "heat-velocity" characteristic of muscle contraction was presumed to be a linear phenomenon, a model was proposed for skeletal muscle (A5). A muscle is a simple spring in a viscous medium. This model accounted for the linear inverse relationship between "force-velocity” in that when the velocity of shortening increased the frictional resistance to shortening increased in direct proportion (2A). It was soon demonstrated however, that a simple linear relationship between the velocity of shortening and force generated or heat dissipated does not generally ll exist (53). As the speed of shortening increased, it was found, the force decreased not in a linear fashion as would be the case if viscosity alone were concerned, but rather in an exponential fashion. To explain the exponential ”force-velocity" relationship,Hill (28) altered his muscle model somewhat. He proposed that a muscle has active contractile elements in series with passive elastic ones. The former obeys Hill's equation of linearity; the elastic elements caused the nonlinear exponential relationship. However, it was again shown that Hill‘s equation was inadequate to explain the inverse "force—velocity" relationships. Levin and Wyman (53) devised a method whereby the elastic components of a muscle were held constant during a muscle twitch. In this way the contractile elements could be studied alone. They found that the ”force-velocity” graphs were not linear but exponential. It was, therefore, concluded that the inverse exponential ”force~velocity" characteristics of contracting muscles were not due solely to the elastic component but also to the contractile elements. Hill (A6) stated that the viscous theory of muscle contraction must be dismissed. The muscle may still have viscoelastic properties but they are less important in muscle behavior than the other prOperties of shortening heat and energy regulation. He concluded that the active muscle is a two component system containing an apparent damped element (contractile element) in series with the undamped elastic one. 12 Functional Anatomy and Movements of the Heart Anatomy Knowledge of the functional anatomy of cardiac contraction is essential for an understanding of cardiac action. Actually, the two ventricles have different anatomical and functional characteristics. The energy released during systole of the heart represents the combined effects of various bundles of myocardial fibers. Contribu— tion of each bundle depends not only on its contractile power but also on its anatomical orientation with the cardiac walls (69, 75). Four valve rings of dense connective tissue join to form a fibrous skeleton of the heart. The atrial and arterial trunks are attached to the superior surface of this fibrous skeleton; to its inferior aspect are fastened the arteriovenous valves and ventricular chambers (69). The atrial musculature is thin and arranged as bands radiating from the sulcus terminalis. The atria have two muscular systems, one common to both atria and encircling them, the other arranged at right angles and independent for each atrium (75). From a functional point of view, the ventri— cular musculature has two groups of myocardial bundles, the spiral muscles and the deep constrictor muscles (71). The superficial spiral muscles, which arise from the mitral and tricuspid rings cover very thinly almost the entire surface of both ventricles to a depth of about 1 mm. They course l3 diagonally around the surface of both ventricles to converge at the apex where they are strongly twisted and where they make up the full wall thickness. They penetrate to the interior of both ventricles to form its inner thin layer of spiral muscle and the lower third of the interventricular septum. They Spiral upward in reverse directions to form the papillary muscles from which fibrous tendons attach to the valve leaflets. The inner and outer spiral muscles follow oblique directions about 900 apart since they spiral in opposite directions. As they contract, the oblique traction by the outer layer is opposed by tension in the opposite direction by the inner layer. The net result of their action is a shortening of the ventricular cavities longitudinally rather than a rotation of the ventricles (70). Interposed between the thin exterior and interior Spiral muscles, are the deep constrictor muscles which make up the basilar two-thirds of the septum and lateral wall of the left ventricle. In the right ventricle these deep circular fibers form a thin middle layer but its contribution to thickness is small compared to that of the inner and outer spiral layer. Because the left ventricular wall contains a large mass of circularly arranged constrictor fibers, its contraction would be expected to result predominantly in a reduced ventricular diameter with minimal shortening from apex to base whereas in the right ventricle with its dominance of spiral muscle, the ventricle should shorten with little movement of its lateral wall (72, 73, 7A). l-l 1A The configuration and contraction of the right and left ventricular chambers are very different. The right ventricle resembles a pocket fastened to the periphery of the convex intra-ventricular septum. During contraction, the free wall conforms more closely to the convex septum, ejecting blood into the pulmonary artery and at the same time evacuating most of the blood contained around the periphery of the chamber (75). The left ventricle resembles more of a cylinder with a conoid segment at the apical end. Systole produces primarily a reduction in the diameter of the chamber. Shortening of the ventricle plays a minor role in the systolic ejection (75). Ejection of blood by the right ventricle is accom- plished primarily by a shortening of the free wall drawing the tricuspid ring toward the apex of the heart. Changes in the width of the right ventricular chamber are relatively slight but may be significant due to the large surface area between the interventricular septum and the free wall of the ventricle (7A). The thick constrictor muscles encircling the left ventricular cavity are probably responsible for a major portion of the left ventricular wall thickness. Mgvements of the Heart During Contraction In studies on muscle movement of the heart (69, 73), tiny metal markers were placed on the epicardium and their l5 movements investigated. It was shown that the movement of the markers located in the free walls of the ventricles may be described in two directions: (1) toward the apex (parallel with the wall); (2) toward the interventricular septum. In the right ventricle longitudinal shortening of the free wall was the predominant movement with little reduction in right ventricular width. Thus, metal markers on the free wall moved primarily toward the right ventricular apex. In contrast, the markers on the free wall of the left ventricle moved obliquely toward the apex and toward the interventricular septum indicating a simultaneous reduction in width and length of the chamber. According to Rushmen}et_al, (7A),there are but two functional groups of muscle in the heart: (1) the spiral muscle which forms the internal and external investment; i (2) the deep constrictor muscles. Simultaneous shortening ; of the internal and external layers of the spiral muscle do not produce rotation since the oblique tension exerted by each layer is mutually counteracted. The result of their combined action is to shorten the long axis of the chambers. On the other hand, the deep constrictor muscles act to reduce circumference. Since the deep constrictor muscles are much more powerful in the left ventricle than in the right, the left tends to be compressed in width to a greater extent than the right. 16 The different muscle layers, because of their arrangement in the heart, must slide past one another, However, it has been impossible to demonstrate this since the individual muscle layers are very difficult to locate and/or separate. Evidence has been presented by Rushmer, et_al. (7A) that during systole, the myocardial fibers in different layers do pull against each other and apply stretch to the connections between them. This fiber stretching represented potential energy which was wasted as far as systolic ejection was concerned. However, as the ventricles begin to relax, this potential energy was used to return the ventricular chambers toward their diastolic dimensions, and ventricular filling began immediately. This mechanism was more effective in the thick walled left ventricle. Changes in left ventricular diameter during the cardiac cycle in unanesthetized dogs, using variable inductance gages, has been described by Rushmer (70). He found that there was an increased ventricular diameter during the early filling period, followed by a plateau- duration of slow filling, terminated by a small increase during artial contraction and a rapid increase at the beginning of systole. After this, the ventricular diameter decreased during systole. Rushmer‘s (70) data on ventricular diameter suggested that no real isometric stage of cardiac contraction (as first suggested by Wiggers) existed. He concluded that a 17 more appropriate term would be isovolumic. The volume of blood in the ventricles remained constant, however, the shape of the heart changed during the period of isovolumic contraction. Most hollow elastic structures tend to assume a more Spherical shape as their internal pressure increases and the abrupt increase in ventricular diameter, shown by Rushmer to occur at the onset of ventricular systole, might be due to a rounding and shortening of the chambers (13). Application of Skeletal Muscle Mechanics to Heart Muscle Force—Velocity Relationships of Skeletal and Heart MuSCle In the past few decades, much information has been recorded concerning the mechanics of skeletal muscles (10). Only recently this information has been applied to heart muscle (30, 82). The acquisition of data for analysis of heart muscle mechanics, on a level comparable to that for skeletal muscle, is limited by the relatively compli— cated geometry of the heart and the consequent difficulty of making certain (isotonic or isometric) measurements. The use of isolated heart papillary muscle (a segment of the myocardium with parallel fibers, reasonable dimensions and stable performance when studied in vitae (l, 39), though possibly introducing other limitations (removal from the body and not perfusing), appreciably diminishes the problems present when examining the intact heart muscles. l8 / It is well known (28) that an increase in Skeletal muscle fiber length strenghtens the force of contraction. Sonnenblick and McCallum (82) have shown that cardiac muscle increases its force of contraction when the fiber length is increased. The inverse relationship between force and velocity of shortening comprises one of the most fundamental properties of the contractile system of skeletal muscle (A8, A9). The papillary muscle of the feline heart also is reported to show an inverse relationship between force and velocity of shortening (82). There are differences, however, between cardiac and skeletal muscle mechanics. Sonnenblick (83) has demonstrated with papillary muscles that an increased initial length of tflmecardiaclnuscle increased the maximal rate of tension rise. This does not occur in skeletal muscle. An increased frequency of stimulation of the papillary muscle also increased the maximal rate of tension rise. Again, this is not true of skeletal muscle (83). None of the physical factors that changed the contractile force in skeletal muscle (except temperature) altered its maximal velocity of contraction. In cardiac muscle an increased initial muscle fiber length, higher frequency of stimulation, or a change in chemical environment (calcium, norepinephrine) all may alter the maximal rate of force rise (58, 82, 87, 85). 19 Myocardial Contractility The Need for Definition of Terms Though the term myocardial contractility is often used, it is seldom defined and almost never in terms that are generally applicable. Most workers appear to think of changes in myocardial contractility in terms of some index appropriate to the conditions of their experiments rather than in terms of the fundamental properties of the muscle itself. For example, investigators (57, 19, 52, 65, 7A, 77, 78) have defined myocardial contraction in-terms of cardiac output, stroke volume output, work done, . ventricular pressure, as an increase in external stroke A work, as an increase in external stroke power from a given end-diastolic fiber length and finally as a combination of ventricular diameter and pressure as well as accumulated work and power. While these definitions and many others are useful under the conditions of the experiments for which they were devised, they are not suited to experiments in which isometric or isotonic contractions take place. These indices all give some indication of heart performance. However, the measurements are indirect and may not be measuring what the heart muscle is doing at all. For example, cardiac output is not necessarily dependent upon only the force or velocity of contraction of the heart muscle, but also is dependent upon such factors as peripheral resistance, venous return, and end—diastolic volume. 20 A Useful Definition of Myocardial Contractility It is not easy to describe myocardial contractility in terms that are generally applicable. A complete description of the contractility of a muscle, whether skeletal or cardiac, seems to require the use of four variables, all of which may change simultaneously during the course of a Single contraction. The usual four variables are: (l) tension in the muscle; (2) the velocity of shortening; (3) fiber length, and (A) the time after excitation (85). Blinks and Koch-Weser (8) believe that similar con- siderations can be applied to cardiac muscle but because there may be no plateau of full activity, it seems more meaningful to formulate them somewhat differently. They suggest that changes in myocardial contractility be defined as changes in the performance of the heart that arise from changes in the relationships among force, velocity, fiber length and the time after excitation. Most investigators of myocardial contractility are inclined to believe that variation in heart performance arising simply from a change in physical conditions outside the contractile system (changes in the tension developed, the work done, or the distance shortened) does not necessarily reflect a change in myocardial contractility. For example, changes in the tension developed with changing fiber length (Frank—Starling phenomena) are not considered to represent variations in myocardial contractility, nor are differences .— .-—~.—-_ .—_..:i; ii: .. 21 in the work performed by isotonic contractions against differing afterloads (81). When the duration of the ”active state" changes, a contractility change is thought to occur, whether or not the maximum isometric tension increases. Changing fiber length does not alter the duration of the active state (87). The "active state," which characterizes the properties of the activated contractile elements is very important in defining myocardial contractility. The definition of myocardial contractility lies within the chemical processes (from which the "active state" is derived) which cause the contractile elements to shorten and develOp tension. Very little is known about these chemical processes. The passive series elastic elements in heart muscle are characterized by the heart's load—extension properties (13, 87). The active contractile elements are best characterized in the terms of four dimensions: force, velocity, instantaneous muscle length and time. The identification of the four variables of the "active state” and their quantification provides a framework for the evaluation of myocardial performance (87) and is a rational basis for defining myocardial contractility. Myocardial Contractility as Defined by Changes in the First Derivative of Ventricular Pressure Pulses Some investigators, in attempting to define myocardial contractility, have used the first derivative of the intraw ventricular blood pressurecnnnma as an index of heart 22 performance (23, 63, 6A, 70, 76, 79, 90, 91). The first derivative of the intraventricular blood pressure pulse for a complete cardiac cycle simply gives the rate of change of pressure as a function of time. In other words, the first derivative gives the velocity of pressure build-up during systole expressed as mm. Hg./sec. The velocity of pressure change is usually not constant during any phase of systole but is accelerating for approximately one-half of systole and decelerating for the remainder. In one particular study (33), a summary of the changes in the first derivative of the intraventricular pressure pulse are given for a complete cardiac cycle. This was done during human open chest surgery. A needle, connected to a pressure sensing transducer, was inserted into the left ventricle. It was found that during ventricular diastole, when the rate of change of ventricular pressure is slow, the first derivative (dp/dt) is flat and about zero. With the onset of contraction in the left ventricle, dp/dt increased slowly for several milliseconds and then rose smoothly to reach its peak derivative near the midpoint of the isovolumic contraction period. In the right ventricle it was found that dp/dt exhibited either a notch or an inflection on its ascending limb. The dp/dt fell abruptly to values far below zero during late systole. The peak values for rate changes in left ventricular pressure (dp/dt) were within the range from 8A1 to 3,239 mm. Hg./sec. The authors stated -I 23 V that the rate at which ventricular preSsure developed was a fundamental property of the ContraCting myocardium. Sonnenblick (87) has previously demonstrated on cat papillary muscle, that the initial fiber length at the onset of contraction greatly influenced the maximal rate of force rise. Reeves, etfial. (63) were interested in determining how much initial fiber length influenced maximal rate of pressure rise in the intact dog. The data suggest that the maximal rate of pressure rise (dp/dt) is altered by the same mechanical conditions in the intact heart as Sonnenblick has described for the isolated papillary muscle. Contraction of isolated heart muscle demonstrates two prominent characteristics. First, under constant load, steady frequency of stimulation and constant inotropic state, the rate of force development increases with increased fiber length. In the intact ventricle, maximum dp/dt increased as left ventricular end—diastolic-pressure was elevated. Second, in isolated heart muscle, at constant initial length, the rate of force development increases during norepinephrine infusions and by digitalization. In eachinstance, a marked increase of maximum dp/dt occurred despite a fall of left ventricular end-diastolic—pressure. Some of the factors that influence the maximum dp/dt are fiber length, mean aortic pressure and heart rate changes "I M 2A without changes in left ventricular end-diastolic pressure and aortic diastolic pressure. It was suggested by Reeves and Hefner (6A) that changes in maximum dp/dt are not a specific index of myocardial contractility. However, changes in maximum dp/dt can, and frequently do, reflect changes in myocardial contractility. The authors preferred to define myocardial contractility as follows: when, from any lowered or constant end—diastolic pressure, the maximum dp/dt rose, an increase of myocardial contractility was considered to have occurred. In the Open chest dog, Reeves and Hefner (6A) in- vestigated three cardiac variables: (1) end-diastolic stretch (using Rushmer's variable resistance gages); (2) contractility (Brodie—Walton strain gage); and (3) intrae [A ventricular pressure. The results show that the maximal rate of pressure rise in the ventricle during isometric systole is a direct linear function of the product of the end-diastolic stretch and contractility of the ventricular myocardium (measured with strain gage transducer). The maximal lepe of the isometric contraction phase of the left ventricular pressure pulse was found to range from A56 to 6,610 mm. Hg./sec. Other investigators (63, 6A, 79) have studied the rate of rise of ventricular blood pressure in an attempt to quantify contractility of the myocardium. Their results suggest that the ratio dp/dtzintegrated isometric tension -|l 25 is such a quantification. This ratio was used because it gave an index of myocardial contractility which was in— dependent of changing end—diastolic pressure, afterload and myocardial work. This index then facilitates a distinction between the Frank-Starling mechanism and true inotrOpic shifts in myocardial function. Siegal and Sonnenblick (79) suggest that the ratio of dp/dt,to instantaneous pressure should be considered a good index of contractility. They concluded that fiber length is the most important factor in determining the maximum velocity of muscle Shortening. Measurements of Cardiac Performance by Strain Gage Transducers Types of Strain Gage Transducers In investigating the mechanical prOperties of ventricular muscle, two types of strain gage transducers have been used: the Walton-Brodie strain gage arch (9) and the spring Cushny lever (92, 55). The Cushny lever was used for both isotonic and isometric studies. The Walton—Brodie gage measured only isometric tension. Both gages were sutured directly to the surface of the heart, and usually sensed isometric systolic tension of approximately fifty grams (6, 17, 28, 92). In a particular experiment (17), on the Open chest dog, the Walton—Brodie gage was sutured on various sites of both the left and right ventricle. The results of the 26 investigation have shown that recordings of percent change of contractile force from any given area of the ventricles are representative of the contractile activity of the entire syncytium. The authors (17) have further demonstrated that increasing the initial length of the muscle segment between the two points of attachment to the strain gage arch results in an increase in the force recordings. However, at a 30 percent increase in initial length, the force plateaus and a further increase in muscle length had no effect. Stretching the segment of muscle under the transducer by approximately 30 percent reduced the variations of force recordings-between different sites of attachment of the gage as well as between dogs. With chronically implanted strain gage arches (9), the systolic force commonly recorded at the time of surgical attachment of the arches was on the order of 50 grams. This force was found to be reduced with time after surgery due, supposedly, to the gradual loosening of the suture attach— ments. It was for this reason that, in the closed—chest observations, results were expressed in terms of percent change in contractile force rather than in gram tension. In suturing the strain gage arch onto the heart most investigators used the following technique: an incision was made between the left Ath intercostal space. The heart was rotated to expose fully the anterior aspects of the right ventricle and the pericardium was resected over this area. 27 The arch was attached to the anterior surface of the right ventricle by cotton thread sutures, one set near the A—V sulcus and the other near the septum. Two to three sutures were laid at each point, threaded through the drilled holes in the "feet” of the arch and tied. Potential Limitations of the Strain Gage Transducers One of the potential limitations of the strain gage arch (Walton—Brodie strain gage arch) for investigating the mechanical properties of ventricular muscle is that the muscle segment actually under the gage is probably not functionally independent of the remainder of the heart and may therefore by influenced by the activity of the adjacent myocardium. It has been Shown, however, that the electrical and mechanical activity of the entire heartltmwflfmxiconstant while the length of the small segment of myocardium under study was altered (6). The response of the transducer is undoubtedly influenced by the absolute quantity of myocardium to which the strain gage arch is attached, i.e. the number of muscle fibers included within the sutures. The chief complication of the chronic implantations of strain gage arch thus far has been adhesions which tear out the sutures holding the strain gage to the muscle and break the lead wires. 28 Characteristic Investigations with the Strain Gage Transducer The effects of catecholamines on myocardial contractility during experimental adrenal insufficiency, were tested by Lefer and Sutfin (51). A modified Walton— Brodie strain gage arch was sutured to the epicardium of the left ventricle between the main coronary branches. The sutures holding the gage were inserted into the ventricular wall to a depth of A—6 mm. The muscle segment was stretched about 33 percent of its normal diastolic length. The stretching increased the absolute value of the contractile force, but since relative changes were tested, this did not effect the results of the measurements. The stretching was said to reduce possible artifacts produced by excessive dilatation of the heart. The ventricular systolic contractile force was about 59 grams of tension and the diastolic about 16 grams post surgery. In other typical studies (A, 52) the strain gage arch (Walton-Brodie) was sutured to the left ventricle, the chest was closed and the dog was allowed to breathe spontaneously. The effects of quinidine and procaine on myocardial contractility (contractile force) were tested. Results were again stated as relative change in contractile force. The authors maintain that at present the recorded curve from the strain gage is the most direct measure of myocardial contractility. 29 Reeves and Hefner (6A) have investigated the relationship of contractile force and myocardial Contractility in the intact mammalian heart. The strain gage was sutured to the heart and the chest remained open during the experiment. Recordings from the strain gage were differentiated electrically and also integrated manually. The maximal rate of tension development was measured before and after injection of epinephrine. It was found that not only did the total tension increase, but the rate of development of tension increased. The correlation between Contractile force and the maximal rate of force rise was r = .A5. CHAPTER III CHANGES IN RIGHT CARDIAC CONTRACTILE FORCE AND RIGHT INTRAVENTRICULAR BLOOD PRESSURE IN RESPONSE TO EPINEPHRINE AND LARGE VESSEL OCCLUSION Purpose of Investigation The purpose of this portion of the present study is to investigate the capabilities and limitations of a strain gage transducer (S.G.T.), when sutured onto the surface of the heart, for evaluating myocardial performance. First, a comparison was made of simultaneous changes in right ventricular contractile force, as sensed by the S.G.T., and right intraventricular blood pressure after injections of epinephrine. If a good correlation exists between the force and pressure variables, the S.G.T. probably is measuring correctly then, one aspect of cardiac performance. Next, the blood pressure within the ventricle was altered and its effects on myocardial contractile force (by the S.G.T.) were studied. In the first experiments of the study, the force of contraction was augmented by the addition of epinephrine. The independent variable was the force of contraction and a pressure change within the ventricle was the dependent variable. In the second portion of the study, the pressure was indirectly or mechanically altered in the ventricle and was, therefore, the independent variable. 30 31 In this case then, the S.G.T. force data were examined as a function of pressure changes in the ventricle. Materials and Methods Experimental Animals Three mongrel dogs were used in these experiments. The dogs were anesthetized with a 6% solution of sodium pentobarbital (30 mg./Kg.). Surgical Techniques The heart was exposed by a midsternal incision and artifical respiration was maintained. The pericardium was opened to expose the right ventricle. Two similar strain gage transducers eppendices A and 3 were sutured to the surface of the right ventricle. One gage was positioned parallel to the most obvious direction of myocardial shortening. The other gage was adjacent and perpendicular to the first. Sutures attaching the strain gage transducers to the surface of the heart penetrated the entire wall of the right ventricle. The suturing material was 000 Mersilene. Instrumentation The right ventricular blood pressure was monitored by a Statham blood pressure transducer (model P 23 A) to which was attached a piece of polyethylene tubing (6 inches long) with an 18 gauge needle (1 1/2 inches) fastened to one end. The needle was inserted directly into the apical portion of the right ventricle. 32 Left carotid blood pressure was monitored by a Statham blood pressure transducer (model P 23 A), attached to a polyethylene cannula (9 inches long). All recordings were made on a Grass Model 5 ink writing oscillograph. Epinephrine was injected intravenously into the left femoral vein. To occlude the venous and arterial vessels, lifting ligatures (cotton thread) and glass tubing were used (Rumel tourniquet). Both free ends of the lifting ligature were passed through the glass tube and by pulling the vessel toward the glass,occlusion occurred. Results Force and Pressure Response to Epinephrine Approximately 15 seconds after the injection of 2.5 ug epinephrine into the left femoral vein, the force of contraction, detected by the S.G.T., and the pressure in the ventricle began to rise as shown in Figure l. The force and pressure values rose rapidly, plateaued and began to decline in a simultaneous manner. The force generated by the myocardium, under the S.G.T., was found to be higher for the gage attached parallel to the direction of most obvious ventricular shortening, (S.G.T.v) than for the gage sutured perpendicular and adjacent to (S.G.T.L) the first. However, the S.G.T.L sensed a 70 percent increase in force of contrac- tion, after injection of 2.5 ug epinephrine, as compared to 57 percent sensed by the S.G.T.v. 33 Figure l.-—Intravenous injection of 2.5 ug epinephrine: Response of (from above downwards); (a) left carotid blood pressurep (b) contractile force in direction of most obvious contractmn (S.G.T.v), (c) contractile force perpendicular to b. (S.G.TJJ. (d) right ventricular blood pressure. 0 55511:, I. r ." I'm-”cf- . A - S .. guh', w. He. Pacssuae G_M. FORCE MM HG. PRESSURE 3A I45? I55 ’ I25 llb |O5 2| 20 I9 I8 I? IS LF. CAROTID 8L. PR. A A A \ S.G.T. (v) 'vvvvvvvr VV'V'Yf 7"VVVV S.G.T. (1.) 'V'VV'I i u 0‘ V'vvvvv'v RT. VENTRICULAR 8L. PR. 22 WNT. l 1 l l l 4 32 40 4e 56 INJECTION (SECS) l l 8 I6 TIME POST 2 L “l—w ’1. “ 35 The right ventricular blood pressure increased by 70 percent from its control value. Under the conditions of this experiment then, the percent increase in force and pressure were almost identical. The carotid blood pressure rose from its control value of 110 mm. Hg. to a maximum of 1A0 mm. Hg. for the three dogs, an increase of 27 percent (Table 1). Figure 2 Shows a plot of the increase in myocardial contractile force compared to the increase in right ventri— cular blood pressure. The relationship is compared for both gages. The results Show a linear relationship between force and pressure, S.G.T.v, r = .95 and for the S.G.T.I, r = .92. The above study was repeated with increased dose of epinephrine to 5 ug. Results are shown in Figure 3. Force and pressure variables again appear to change simultaneously. The force sensed by the S.G.T.v was again greater (5 grams) than from the S.G.T.L, Table 1. In plotting the rise of force against the rise of pressure for both strain gages, Figure A, again a good linear relationship is shown, S.G.T.v, r =.9A, and for the S.G.T.I, r = .96. Force and Pressure Response to ”Venous Occlusion" The effect of clamping the superior vena cava, inferior vena cava and the azygos vein ("venous occlusion”) on the intraventricular blood pressure and myocardial contractile force sensed by the S.G.T.‘s is Shown in Figure 5. “I 36 Figure 2.—-Comparison of changes in cardiac force and ventri- cular blood pressure in response to 2.5 ug epinephrine. I MM. HG. ) PRESSURE 37 38+ I ° 0 s ..(l) / 34+ 0 a Rat! 30+ / /S.G.T. (v) ° /0 no .05 / . 26+/ V / 4. +— 4- + -o- ID l2 l4 I6 IS 20 22 FORCE (GMS) 38 Figure 3.——Intravenous injection of 5.0 ug epinephrinegResponse of (from above downwards);(a) left carotid blood pressure, (b) contractile force in direction of most obvious contraction (S- G.T.v), (c) contractile force perpendicular to b. (S.G.T.L), (d) right ventricular blood pressure. esp-3:55 5 |—— :‘5 .2 ’:l V s. ~- _.- \ I r ‘3‘ 39 ISOE' - “M Hg. : LE CAROTID cum. I ultrmRE :com ”0;- C S.G.T. (v) GM. 20L ToRcE E E 5.0 UG. EPI. 12:- GM I5:- S.G.T. (l) FORCE I E 4|} MM. +£6.33. thaw? RT. VENTRICULAR BL. PR. 25 I I l 1 l 48 I6 24 32 40 TIME POST INJECTION ——ESEC§5-— A0 Figure A.-—Comparison of changes in right cardiac force and ventricular blood pressure in response to 5.0 ug epinephrine. . u AAAAA S. 6.4 (v) R- .04 Al . \:| o\ g: k 0\ d w o \ \ ‘ \ .1 °\ \ .. \ .. \ . :1 3, a $131 :11 :1, NI OH 'WW BHRSSBHd 27 I!) N '0 N 3" (D. 2 23 LU p ”O 0: :53 '2 A2 Figure 5.——Occlusion of superior and inferior’venae cava and azyzos veins: Response of (from above downwards); (a) left carotid blood pressure, (b) contractile force in direction of most obvious contraction (S.G.T.v), (c) contractile force perpendicular to b, (S.G.T.L), (d) right ventricular blood pressure. ‘fi A3 IOOTML\\ .\ u: CAROTID BL. PR. u“, "G. \\ 2°;- \S.B.T. (V) I. A / *— GM. ,0 NO VENOUS RETURN S.G.T. (1) on. a 22-c MMHGMA— RJ’. veurmcuua sum. ‘ F : 1‘6 5? I 52 TIME POST OCCLUSION (SECS) AA a one Hponmo ewe .mm .se oae .mm .es mHH amiwmesm sew .mm .ee oea .mm .ee OHH amammesa . cc . . cc . ezaa .mm .88 m: .wm .EE aw WLSWmmWM eow .mm .88 Am .mm .88 mm WLSWchM seas .ee m.am .ee e.a A Womom e0. .ea as .ea as A Womem O >0 0 O O .l. >0 0 0 saw .am Am em a.ea Womom esm em am .Em ea Womom .nocH czam> msfim> .socH c5am> msam> & .xmz Homecoo canmflnm> R Essfixmz Hospcoo cflnmflsc> mnfinngmcfigm m5 o.m ccfissqccflam m3 m.m II. IIIIIIIIIIIIIIIIIIIIIIIIII, - .cnzmmmhg BOOHQ amazoflnpsc> Ithaca psmfls pct momom cawpomhp: oo omflpnmo pgwflp no ceasnncsflam ac mpocmmmll.fl magma 45 The experiment shows that both pressure and force measurements decline almost simultaneously. The right ventricular blood pressure dropped rapidly from a control of 21.A mm. Hg. to 6.3 mm. Hg. The myocardial contractile force, as sensed by the S.G.T.v, declined from a control of 12.8 grams to 9.A grams. A drop from 9.A grams to 5.A grams was registered by the S.G.T.I. A drop in myocardial contractile force during venous occlusion to the heart is probably due in part to a lowering of the pressure in the ventricle or a decrease stretch on the heart muscle (Frank—Starling phenomenon). However, various other parameters such as decreased coronary flow and nervous reflexes should be considered before any con- clusive statement can be made.Therefore, a drop in pressure within the ventricle does not necessarily mean that the pressure directly influences the recordings of the S.G.T., there may in fact be an actual drop in force as generated by the myocardium. In this experiment (”venous occlusion") the force as sensed by the S.G.T.v was greater than that sensed by the S.G.T.I, again Showing a quantitative force difference due to gage placement on the heart. The correlation coefficients comparing force and pressure data were r = .85 for the S.G.T.v and r = .96 for the S.G.T.I. This again Shows a close relationship between the two variables. A6 Figure 6.——Occlusion of the descending aorta (mid—thoraticfl Response of (from above downwards); (a) left carotid blood pressure, (b) contractile force in direction of most obvious contraction (S.G.T.v), (c) contractile force perpendicular to b, (S.G.T._|_), (d) right ventricular blood pressure. A7 I7 5I LE CAROTID BL. PR. MM. HG. etc 95 ~com. “3‘ ' S.G.T. (V) com. GM. " occwoeo oesceuomc AORTA GM. S.G.T. U.) com; AW 8 fl 4- RT. VENTRICULAR 3L.PR. I6 -CONT. MM. HG. | 1 1 1 l 1 2 4 3 I2 I6 20 TIME POST OCCLUSION (SECS) A8 Force and Pressure Response to Occlusion of the Descending Aorta The occlusion of the descending aorta (mid-thoracic region) resulted in a rise in both carotid and ventricular blood pressure as well as a slight rise in right ventricular contractile force. The carotid blood pressure rose from a control value of 90 mm. Hg. to a maximum of 160 mm. Hg. The force (by S.G.T.v) rose from a control of 13.9 grams to a maximum of 16 grams. The "perpendicular" gage (S.G.T.L) indicated control force of 8.2 grams, which rose to a maximum of 9.3 grams. The right ventricular pressure increased from a control of 15.7 mm. Hg. to a high of 18 mm. Hg., Table 2. Table 2.-—Occlusion of large veins to heart, effects upon right myocardial contractile force and right intraventri— cular blood pressure. Variable Contr. Value Minimum Value % Change Force 9.A m. — 27% S.G.T.v 12.8 gm. S Force 5.A m. - A2% S.G.T.v 9.A gm. g Pressure H . 6,3 mm.Hg. - 71% Rt. Vent. 21'” mm’ g Pressure 90.0 mm. Hg. 32.0 mm. Hg. - 6A% Carotid A9 Table 3.——Occlusion of descending aorta, effects upon right myocardial contractile force and ventricular pressure. Variable Contr. Value Max. Value % Change Force 1 9 l6 S.G.T.v 3° gm‘ gm” 15% Force 8 2 1 7 S.G.T«_I_ . sm- 9-3 em. 30 Pressure Rt. Vent. 15.7 mm. Hg. '18 mm. Hg. 1A% Pressure Carotid 90 mm. Hg. 160 mmg. Hg. 77% Force and Pressure Response to Occlusion of the Ascending Aorta The occlusion of the ascending aorta resulted in a fall in both carotid and right ventricular blood pressures and a rise in ventricular force recordings, Figure 7. The carotid blood pressure dropped from a control value of 90 mm. Hg. to a low of 15 mm. Hg. The right ventricular pressure dropped from a control value of 11.6 mm. Hg. to a minimum of zero. The force, from S.G.T.v, shows a rise from 13.9 grams to 21.2 grams, whereas the S.G.T.I rose from 9.7 grams to 17.9 grams, Table A. When the ascending aorta is occluded suddenly it appears that the force of myocardial contraction is increased probably by sympathetic discharge by way of the 50 Figure 7.——Occlusion of the ascending aorta: Response Of (From above downwards); (a) left carotid blood pressure, (b) contractile force in direction of most obvious con- traction (S.G.T.v), (c) contractile force perpendicular to b, (S.G.T.L), (d) right ventricular blood pressure. I40 MM.HG. GM l7 GM. '5 "I b 51 IE... V\ . LE CAROTID BLPR. ochuoeo ASCENDING man —_ — S.G.T. (v) RT VENTRICULAR BL. PR. I I 4 l2 20 28 36 TIME POST OCCLUSION (SECONDS) l 52 Table A.--Occlusion of ascending aorta, effects upon right myocardial contractile force and ventricular pressure. Variable Contr. Value Max. or Min. Value % Change Force S.G.T.v 13-9 smS- 21-2 smS- + 53% Force 0 o + LIO S.G.T.L 9.7 gms. 17 9 gms 8 7 Pressure 0 o o H o '- 1000 Rt. Vent. 11'6 mm' Hg 0 0 mm g 7 Pressure 0 u o H o -' 8 % Carotid 90.0 mm. Hg 15 0 mm a 3 carotid sinus reflex. The factors involved in this kind of response will be discussed later. fierce and Pressure Response to Occlusion of the Pulmonary Artery The occlusion of the pulmonary artery resulted in a fall of carotid blood pressure and a rise in the myocardial contractile force and right ventricular blood pressure, Figure 9. The carotid pressure declined from a control value of 100 mm. Hg. to 60 mm. Hg. since no blood was being pumped to the systemic vessels. The myocardial contractile force, from the S.G.T.v, rose from a control of 10.2 grams to a maximum of 13.9 grams, whereas the S.G.T.L indicated a rise from 10.A grams to 2A.l grams. The right ventricular pressure rose from a control value of 19.3 mm. Hg. to a maximum of 65.7 mm. Hg. or a 235 percent increase, Table 5. 53 Figure 8.--Occlusion of the pulmonary artery: Response of (from above downwards);(a) left carotid blood pressure, (b) contractile force in direction of most obvious con- traction (S.G.T.v), (c) contractile force perpendicular to b, (S.G.T.I), (d) right ventricular blood pressure. 5A ”SIM ‘ LE CAROTID 91.952. MM. HG. I2 " S.G.T. (V ) GM. IO " 23- 0C 0 LUDED PULMONARY ARTERY 45 RT. VENTR ICU LAR BL. PR. MM.HG. 1 l 1 L l 5 4 l2 20 28 36 TIME POST OCCLUS ION (SECONDS) 55 Figure 9.-—Graph showing comparison of force displacement transducer (F.D.T.) and strain gage transducer (S.G.T.) when sutured on the surface of frog gastrocnemius muscles. Ordinate is percent increase in force. Abscissa is stimulus strength at 6 msec and 0.5 cycle per second. 56 7.59: w 0 m3 DEE/Hm em on m. N. m 4 q q d H q mdowac‘ J’ . .oxoo 1< 03%."; EEOC. mmamwmxd _ . / \ or ssfio. \ < «o to .33.? So 00. i i “l "W - mmommmmd i ‘ momOm homo... / \ .sowom m r . w _ A. - oou i. . n , _ A I? < o 91? N Jo _ in R < mOhDaEOU mm Fm 7A Figure 12. A.——A scheme showing the relation between (a) aortic blood pressure (b) right ventricular blood pressure, and (0) its derivative (dp/dt) for a complete cardiac cycle. Listed are three para— meters measured in the study. B.——A scheme showing the relationship between (a) aortic blood pressure, (b) right ventricular contractile force and (0) its derivative (df/ dt) for a complete cardiac cycle. Listed are three parameters measured in the study. 75 AORTIC BL. PR. RT. VENTRICULAR BL. PRESSURE loofmmeJsot , dP/dt ck lfl ' LTIME INTEGAL OF PRESSURE (flu!) 2% CHANGE IN MAX. 49/1" 3. PRESSURE AT MAXdP/dt AORTIC BL. PRESSURE RT. VE NTRICULAR manor: FORCE 75F9szcm df/dt LTIME INTEGRAL or FORCE (Fm 2.x CHANGE m MAX.df/dt 3. FOR CE AT MAX. elf/d! 76 facilitates quantification of this ability of the myocardium to vary its rate of contraction. The results of this study indicate that maximal dp/dt and maximal df/dt (Figure 13) are equally "good" indicators of a decrease in heart per- formance during chloroform inhalation. The correlation (r = .73) between the force and pressure derivatives is good. Not only did maximal dp/dt and maximal df/dt decline during chloroform inhalation’they required a longer period of time after the onset of systole to reach these maximal values. This is shown in the increased durations of the time intervals (T.I.) from the peak of the ECG R-wave until maximal dp/dt and df/dt are developed (Figure 13). The areas under the right cardiac force curves were found to vary differently from those for the right intra— ventricular blood pressure during chloroform inhalation (det and f Pdt) (Figure 13% Part of this is due to the weakness of the contracting myocardium which in turn increases end-systolic volume promoting right heart congestion. Therefore, chloroform causes an increased right intra- ventricular pressure and/or fiber length, as shown by the increased area under the pressure pulse curves. Cardiac Effects of Epinephrine on Force and Pressure Epinephrine has a pronounced faciliatory effect on the ability of the myocardium to alter its rates of contraction and intraventricular pressure rise (Figure l5, l6, l7). Fl _ Figure 13. 77 A.——Inhalation of chloroform; Percent change from. control (ordinate), time in sec. after beginning drug inhalation (abscissa) from above downwards. a b. 0. time d. time e. time f. time . first derivative of pressure (dp/dt) first derivative of force (df/dt) integral of force (det) integral of pressure (det) interval pressure T.I.p interval force T.I.f Typical changes for one dog with measurements every 20th heart beat (see Tables 6, 7, 8, 9, Appendix G). B.——Inhalation of chloroform: Percent change from control (Ordinate), time in sec. after beginning drug inhalation (abscissa) from above downwards. r—«DmQOO‘m . time. time interval force (T.I.f) time integral pressure (det) first derivative of pressure (dp/dt) first derivative of force (df/dt) time integral force (det) interval pressure (T.I.p) Mean for six dogs where measurements were made every 20th heart beat (see Tables, 6, 7, 8, 9: Appendix G). CHANGE FROM CONTROL % O" 34 gs i5? $6, WES—“W Time Post Rhsponse (Sec.) FROM C(NTROL CHANGE i L"..P.RE_SS_URE TJ. FORCE “- .fidt... -AP/Q'ru- df/dt M 1. gé‘rf'fillz 7. 1 Figure 1A. A.--Right contractile force response to chloroform: Top, oscilloscope tracing of control and its derivative contractile force (df/dt). Bottom, tracing of experimental contractile force and its derivative (df/dt). (Sweep speed 50 msec./cm. (abscissa); contractile force 1 cm. equals 15 gms. ordinate). B.—-Response of right ventricular pressure to 0.7 mg ouabain: ‘ Top, oscilloscope tracing of control ventricular pressure and its derivative (dp/dt). Bottom, oscilloscope tracing of experimental ventricular pressure and its derivative (dp/dt)- Scope sweep speed 50 msec./cm. (abscissa); Intraventricular blood pressure 1 cm equals lO mm. Hg. (ordinate). 8O Control Experimental Contractile Force df/dt Contractile Force df/dt 81 Figure 15. A.——Effects of intravenous ephinephrine (5 ug): Percent change from control (ordinate); time in sec. after drug injection (abscissa), from above downward. first derivative of pressure (dp/dt) first derivative of force (df/dt) force at maximal df/dt pressure at maximal dp/dt time integral of force (det) time integral of force (det) time interval pressure (T.I.p) time interval force (T.I.f) :rm m(oo.or7m Typical changes for one dog with measurements every fourth hear beat (see Tables 10, ll, 12, 13: Appendix G). '7 B.——Effect of intravenous epinephrine. a. first derivative of pressure to 5 ug, 2-5 ug and l.25 ug doses. b. first derivative of force to 5 ug. 2.5 ug, and 1.25 ug doses. Plot“ of mean values for 3 dogs from measurements every fourth heart beat (see Table 13, Appendix GA CGIIC .‘cw CHANGE FROM CONTROL ‘7. 82 ’\ I ‘ \ / ‘ \ ~DP/DT / IZO— ’ ,. 50., EPI. I I X / l \\ one? / ’ \\ I I \ 96" I I ‘ P l I ’ I ’ I ’ I 72- I I I I I ,’ ’ I 48W» ’ I / I I . I ” DT / 4- I 2 J] [I ---- 3; OT ,/ / , , "' . /// I, ’I’ O "‘ :j: \ ~\ T.” {L . . -------..n L . 5 IO I5 20 25 3O 72 48 24 % CHANGE FROM CONTROL TIME POST INJECTION (SECS) EPINEPHINE ALL 0°“ .— DP’ OT 2.500. DF/ 01’— 5 IO I5 20 TIME POST INJECTION SECS) 83 Figure l6.——Response of right contractile force and ventricular pressure to 2.5 ug epinephrine. top, oscilloscope tracing of control and experimental cardiac force and its first derivative (df/dt). bottom, oscilloscope tracing of control and ‘ experimental right ventricular pressure and its first derivative (dp/dt). Sweep speed 50 msec/cm. (abscissa), contractile force, 1 cm. equals 15 gms. (ordinate). Intraventricular blood pressure, 1 cm. equals l7 mm Hg. (ordinate). 8A a (u 33.. Control Experimental .—-Force .——df/dt O‘SD Control Experimental a.——Pressure b.—-dp/dt 85 Figure 17. A.—-Effects of intravenous epinephrine: Percent change from control (ordinate), time in sec. after drug injection (abscissa), from right to left. a. changes in time interval of force data to 10 ug, 5 ug, 2.5 ug and 1.25 ug doses. b. changes in time interval of pressure data to 10 ug, 5 ug. 2.5 ug and 1.25 ug doses. Mean for three dogs, measurements every fourth heart beat (see Table ll, Appendix G). B.——Effects of intravenous epinephrine (5 ug) on duration of time interval (T.I.). a. duration of time interval (millisecondS) for pressure data (ordinate). b. duration of time interval (milliseconds) for force data (abscissa). 86 _l O I; EPINEPHRINE EPINEPHRINE 8 h T.| FORCE ‘ ' T.I. PRESSURE I0.0uq I °| 4A: E ug m (5 z < I 0 3| L l L 0 IO 20 30 TIME POST INITIAL RESPONSE Io SECONDS EPINEPHRINE (D O a: O 0) 0 UI O r: 76 K. OI TIME INTERVAL PRESSU RE MILLISECONDS N O A O 4O 50 60 7O 80 90 TIME INTERVAL F'ORCE MILLISECONDS 87 The results indicate, again, that the maximal dp/dt and maximal df/dt are comparable indicators of an increase in heart performance for all dose levels of epinephrine tested (Figure 15, 16). The correlation between these two variables is r = .97. Epinephrine not only promotes an increase in the maximal rate of pressure rise (dp/dt) and force rise (df/dt),it also shortens the period of time, after the onset of systole necessary to reach these maximal values. Figure 17 illustrates~ the decreased duration of this time interval (T.I.) It is. measured from the peak of the ECG R-wave to maximal dp/dt or df/dt. The correlation (r = .71) between these two variables (T.I.p and T.I.f) for all dose levels is good. The change in areas under the right cardiac contractile force tracings and right intraventricular pressure pulse tracings, in response to all doses of epinephrine, was found to increase in a similar manner (Figure 15, [th, IPdt). Effects of Ouabain on Cardiac Force and Pressure The ability of the myocardium to alter intraventricular blood pressure and contractile force is slowly potentiated by the cardiac glycoside ouabain (Figures l8, 19, 20). First derivatives of cardiac pressure (dp/dt) and force df/dt) quantifythis potentiation. The results of this study again show that both dp/dt and df/dt indicate an increase in myocardial performance. The correlation between the two variables is r = .69. 88 Figure 18.--Effects of intravenous ouabaixl (.7 mg): Percent change from control (Ordinate), time in sec. after drug injection (abscissa), from above downwards. a. time integral of force (Ith) b. first derivative of force df/dt c. force at maximal df/dt d. time interval of force (T.I.f) Typical change for one dog with measurements every 20th heart beat (See Table 1A, Appendix G). 89 Amommv ZO_.rom...Z_ km 03 N: vm mm OameS. E. . .1]/] a; #0 Pro #0... 2.4930 2.». w_ Nm % O H V N 9 3 J H O W O O N II. no 0 _| 90 Figure 19. A.—-Effects of intravenous ouabain (.7 ug): Percent change from control (ordinate), time in sec., after drug injection (abscissa), from above downwards. a. time integral of force (det) b. first derivative of force (df/dt) c. first derivative of pressure (dp/dt) d. time interval of force (T.I.f) e. time interval of pressure (T.I.p) f . time integral of pressure (det) Mean for five dogs with measurement every 10th heart beat (see Tables lA, 15, l6, l7, Append1X G) B.——Effects of intravenous ouabain (.7 ug); Percent change from control (ordinate), time in sec., after drug injection (abscissa), from above downwards. first derivative of pressure (dp/dt) pressure at maximal dp/dt . time interval of pressure (T.I.p) . time integral of pressure (det) 0.0C7m ‘ Typical changes for one dog with measurements I every 20th heart beat(see Table 1A, Appendix GA I I % CHANGE FROM CONTROL -___17 N l 5 l O T 7. CHANGE FROM CONTROL 91 . If”! . df/dI MAX. .1.- _' :2 _ _ _ gFL/dlmaxi fl FORCE ’—_‘_ __ .— thngsgugE .IPdr... 4_ I 1 4L uz l40"- I6 a I“ I l 28 56 34 TIME POST RE§flbNSE (SECJ .7um OUABAIN 323- 0 EB 56 S4 |I2 IAO I68 TIME POST INJECTION (SECS) 92 Figure 20.-—Response of right contractile force to 0.7 mg ouabain. 0 top right, oscilloscope tracing of control cardiac force and its derivative (df/dt). \ top left, oscilloscope tracing of experimental cardiac 'force and its derivative (df/dt). bottom, oscilloscope tracing of experimental cardiac force and its derivative (df/dt). Sweep speed 50 msec/cm (abscissa), contractile force, 1 cm equals 15 gms (ordinate). 93 m b Control Experimental (Fifteen minutes post in— a.——Force jection) b.-—df/dt Experimental (Thirty minutes post injection) a.—-Force b.——df/dt 9A Although ouabain increases maximal dp/dt and maximal df/dt,it does not change the time required after the onset of systole for these maximal differentials to be developed by the myocardium. This is evident in that no significant change occurredin the duration of the time intervals (T.I.p and T.I.f) (Figures l8, 19). The correlation between the two variables is r = .21. The areas under the right cardiac contractile force tracings were found to increase, whereas, the area under the intraventricular pressure did not change significantly in response to ouabain (Figure 19). Discussion and Conclusions Widely divergent views have been expressed in regard to the usefulness of the first derivative of intraventricular blood pressure tracings in assessing the performance of the myocardium (33, 6A, 70). Two major objections to the use of maximal dp/dt as a specific index of myocardial contrac— tility are: first, with increasing heart rate, there is a near linear increase in dp/dt (3) and second,at a constant heart rate but with increasing fiber length, there is a similar linear increase in dp/dt (63). However, if heart rate and fiber length are controlled, or remain constant, maximal dp/dt is an excellent indicator of cardiac contractility (12, 79). In this present investigation the first derivatives of myocardial force (df/dt) and ventricular pressure (dp/dt) 95 were compared. During altered heart performance (with CHCl3, epinephrine and ouabain), a high positive correlation between force and pressure derivatives was discovered (r = .76). This indicates that changes in muscle tension are reflected in both df/dt and dp/dt, and that df/dt is a specific index of cardiac contractilityf(when heart rate and fiber length are controlled). For monitoring heart performance,it is suggested here that the strain gage technique is superior and has many. advantages compared to the needle heart puncture method. It is very difficult to prevent needle movement within the ventricle of the heart. Since the ventricle is not spherical the pressure varies from site to site within the cardiac chambers (13). If during cardiac systole the needle's position is altered within the heart, a portion of the recorded pressure fluctuations is due to this movement. Also, during cardiac systole, pressure waves are reflected from the walls of the heart chamber and interfere with pressure measurements,therefore with dp/dt . None of these factors (reverberating pressure waves or movements of the indwelling needle) interfere with the measurement of contractile force and its derivative (df/dt). In the chronic investigation of myocardial contractility (using dp/dt as an index) intra— ventricular pressure measurements (thus dp/dt) are difficult to obtain. No reliable technique is available for chronic intracardiac pressure measurements. The present study 96 demonstrates that the strain gage technique is applicable to chronic measurements of cardiac force (thus df/dt). The time integral, or area under intraventricular pressure and contractile force curves, is also important in defining the performance of the heart. Siegel and Sonnenblick (79, 80) have shown that the area under the ventricular pressure tracings increases directly with increasing fiber length or end-diastolic volume. Reeves, §£_al. (63) have demonstrated that the integrated isometric tension also varies directly with changes in the duration of systole. The results of this present study indicate that the area under the force tracings (Ith) does not always change in a similar manner with respect to the pressure area (det). This suggests that these indices of heart performance (det and det) are measuring two entirely different aspects of cardiac contractility. For example, chloroform decreased the area under the contractile force tracings while the area under the pressure curves remained the same or increased Slightly (Fighres 13, 1A). A probable reason for this is that chloroform causes right heart congestion resulting in a rise of ventricular pressure and increased fiber length increased area under pressure tracings). In the ouabain experiment, integrated systolic force (det) increased whereas ventricular pressure (det) remained constant or declined (Figure 19). Ouabain influences the heart both 97 indirectly and directly. The cardiac glycoside increases aortic blood pressure (22, 15), decreases left and right atrial pressure (20) and finally, by its direct action on arteriolar smooth muscle, increases total systemic resistance (67, 68, ll, 20). The increased total systemic resistance results in a decreased venous return, a reduction in end— diastolic fiber length (22) and a decline in the area under the intraventricular pressure curve. The effect of digitalis glycosides on failing and normal hearts of dogs and humans has been extensively investigated. While there is general agreement that digitalis improves the contractile properties of the failing myocardium, the actions of these drugs on the nonfailing heart are less clear. In the absence of heart failure, acute digitalization either depresses or produces no significant change in cardiac output (20, 67, 88, 9A), whereas in the failing heart,cardiac output is greatly increased (88). Although it has been reported that cardiac output remains constant in the nonfailing heart, the present investigation (using S.G.T.s) demonstrates that myocardial contractile force greatly increases in response to ouabain (Figure 20). This agrees with similar studies where cardiac contractile force, measured by a Brodie—Walton strain gage arch, was always increased (ll, 16, 20, 21, 88, 93). The effects of digitalis on the first derivative of intraventricular blood pressure has recently been investigated 98 (15, 18, 22, 88). These studies by others are corroborated by the present research. Both indicate that maximal dp/dt increases in the nonfailing dog heart in reSponse to ouabain. Furthermore, strain gage transducer studies in this research indicate that ouabairIpotentiateS'the rate of force development (df/dt) by the myocardium. The response of df/dt to ouabain might have been inferred but has not been reported previously. Following ouabain injection heart rate remains almost constant (56, 88), the period of systolic contraction decreases (7, ll, 18, 9A, 99), myocardial oxygen consumption increases and integrated systolic tension is reduced (22) in the noncongested dog. The present data, contrary to Covell, et al. (22), indicate an increase in the integrated area under the cardiac contractile force tracings in response to ouabain. The reason for this disagreement may be due, in part, to different animal preparations. Their procedure included a canine right heart by-pass in which heart rate, stroke volume and mean aortic pressure were held constant. They also observed that the end-diastolic volume and mean aortic pressure decreased in response to ouabain. A decreased time integral of pressure (Figure 19) in the present investigation indicates a drop in end-diastolic volume. The time interval (Figure 21 and Tables 8, ll, 15) from onset of mechanical systole to development of maximal dp/dt or maximal df/dt is usually 30 to 60 milliseconds of duration. The fact that maximal df/dt and maximal dp/dt are 99 Figure 21.--A diagram of the time interval from the peak of the ECG R—wave to the development of the maximal rate of pressure rise. From above downwards. intraventricular blood pressure E.C.G. first derivative of pressure (dp/dt) time interval (T.I.) QJOO‘QJ 100 PRESSURE / dP/dI L _. 6 l 'Tl l i L I 1 O 30 60 90 I20 I50 I80 h P TIME (MSEC) TI = TIME INTERVAL FROM PEAK OF ECG'R-WAVE TO THE DEVELOPMENT OF MAX. dp/dI DOG RIGHT HEART lOl attained somewhat after onset of contraction and prior to onset of ejection (about the middle of the isovolumic stage of the cardiac cycle) makes the measurement of the time interval of particular interest. The reason for this is that according to the force-velocity relationship of muscle contraction (83),the maximal velocity of shortening of the contractile elements should occur at the very onset of contraction when the stretch (load on the muscle) of series elastic elements is least. However, seen quantitatively in the present study, and qualitatively by Reeves, et al. (63), considerable time elapses between the development of the first visible increase in tension in the heart muscle and the attainment of maximum df/dt and/or dp/dt (Figure 21). Why then, is there such a delay in the development of maximal df/dt and/or dp/dt in cardiac muscle? One of the reasons may be the means whereby heart muscle is stimulated (Purkinje system). Rushmer (73) has shown that all of the ventricular myocardium cannot begin to contract simultaneously because all of it is not excited simultaneously. The first portion of the ventricle to contract is the trabeculae carnae and papillary muscles (73). According to Rushmer, the delay in the; ”time interval" is caused by an asynchronous stimulation of the cardiac fibers. During systole more and more fibers are being stimulated and come into play in the tension build-up. Reeves, §£_al. (63) stated that a definite increase in the duration of this "time interval" (10 to 30 102 milliseconds) was noted when the initiation of the heart beat was transferred from the normal pacemaker conducting system (S.A. node) to a pair of pacing electrodes. Wiggers (97), Gilmore, g£_al, (32) and Chardack, et_al. (1A) have also demonstrated that when the heart was paced by ventricular stimulation, the maximal rate of pressure rise was less. Priola and Randall (62) have studied alterations in cardiac synchrony induced by cardiac sympathetic nerve stimulation. They have demonstrated that measurements from the ECG P-wave to the onset of mechanical systole shortened when the stellate ganglion was stimulated in the dog. They (62)saggestediflufl3stellate stimulation increased the conduction velocity over atria nodal tissues and ventricles.Thechoncluded that sympathetic stimulation may promote greater synchrony in the cardiac contraction. Abbott and Ritchie (2) have demonstarted with skeletal muscles, that at the end of the latent period, the part of the muscle at the point of stimulation begins to shorten with its maximal speed. They found that when the stimulus was applied to one end of a muscle, the part of the muscle distant from the electrodes became active only after an extra delay representing the time taken for activity to spread along the muscle to that part. They interpreted this to mean that the shortening of the whole muscle begins gradually. The abrupt change in each fiber is masked by a time dispersion between the fibers. 103 The results of these studies (83, 73, 62, 2) suggest that: a.——each muscle fiber upon stimulation instantaneously contracts with a maximal velocity; b.--all myocardial fibers are not stimulated simultaneously (synchronously) thus, the long duration of the time interval. Theoretically then, if it were possible to stimulate the heart in such a manner that all of the cardiac fibers contracted in perfect synchrony (stimulation of all fibers simultaneously),the first derivative of cardiac force should reach its peak almost instantaneously (Figure 22). These observations on the time interval lead to certain assumptions about the measurement of cardiac contractility. It may be unwise to consider altered cardiac performance as being due solely to a change in contractility of each fiber without considering the possibility that the change was due to a more or less synchronous activation. A change in synchrony of activation is not the same as a change in cardiac fiber contractility. In the present investigation chloroform increased the duration of the time interval in both force and pressure tracings (Figures 13, 1A, Table 8) in all experiments and on all dogs. It is possible that chloroform decreases the conduction velocity of the electrical impulse in the heart. Therefore, the decreased contractility of the heart during inhalation of chloroform may, in part, be caused by greater asynchrony in the cardiac contraction resulting from a lOA Figure 22.——A diagramatic illustration of the right ventri- cular contractile force and its first derivative. From left to the right the force tracing and its derivative (as it would likely look if all fibers in the heart were able to contract simultaneously or synchronously). The normal force and its derivative. are 16 105 50IONI FORCE soI gm/sec. d I A: ‘ O 25 50 75 I00 MILLISECONILS 106 decreased conduction velocity. Since ventricular pacing (63) and chloroform prolong the time interval, it is suggested here that both may cause asynchrony of heart muscle contraction. Epinephrine decreased the duration of the time interval from the peak of the ECG R—wave to the development of the maximal rate of force and/or pressure rise (Figure 15, Table 11). Priola and Pnadall (62) demonstrated that stimulation of the stellate ganglion increases the conduction velocity of the heart muscle. It is likely that epinephrine produces a similar increase in conduction velocity in the heart. Thus, both stellate stimulation and epinephrine injection probably increase the synchrony of cardiac contraction (reflected in the decreased duration of the time interval). The time interval was not altered significantly by ouabain in the present study. However, it did cause an increase in both maximal df/dt and maximal dp/dt. Apparently, therefore, ouabain increases myocardial contractility without altering the synchrony of the cardiac contraction. From the limited evidence presented here, it is likely that the measurement of the time interval between the onset of systole to the development of maximal rate of force and/ or pressure rise is important in the measurement of myocardial contractility. The data so far indicate that this time interval may provide some quantitative information concerning the degree of cardiac synchrony. 107 In summary, it is suggested here, that changes in the time interval, maximal df/dt and maximal dp/dt provide a complete quantitative description of an important property of the myocardium, namely, its ability to vary its rate of contraction. BIB LI OGRAPHY 108 BIBLIOGRAPHY 1. Abbott, B. C. and Mornmaerts, W. F. H. M. A Study of Inotropic Mechanisms in the Papillary Muscle Pgeparation. Journal of General Physiology, A2:533, l 59. 2. Abbott, B. C. and Ritchie, J. M. The Onset of Shortening in Striated Muscle. Journal of Physiology, 113:336, 1951. 3. Akre, E. and Bugge, Asperheum, B. The Effect of Heart Rate on the Myocardial Contractility and Myocardial Oxygen Consumption. Agta, Physiol, Scand: 68, Suppl. 277, 1966. A. Angelakos, E. T. and Hastings, E. P. The Influence of Quinidine and Procaine Amide on Myocardial Con— tractility in Vivo. American Journal of Cardiology, 5 (6)2791, 1960. 5. Anzola, J. Right Ventricular Contraction. American Journal of Physiology, l8A:567, 1956. 6. Aygen, M. M. and Braunwald, E. Studies on Starling's Law of the Heart. VIII. Mechanical Properties of Human Myocardium Studied in Vivo. Circulation, 26: 516, 1962. 7- Benchemol, Alverto, Hugo A. Palmers, Marvins, Tiggett, and E. Grey Dimond. Influence of Digitalization on the Contribution of AtrialSystole to the Cardiac Dynamic at a Fixed Ventricular Rate. Circulation, 32(1):8A—95, 1965. 8. Blinks, J. R. and Koch—Weser, J. Physical Factors in the Analysis of the Actions of Drugs on Myocardial Contractility. Pharmacological Reviews, 15:531, 1963- 9. Boniface, K. J., O. J. Brodie, and R. P. Walton. Resistance Strain Gauge Arches for Direct Measurement of Heart Contractile force in Animals. Proceedings of the Society of Experimental and Biological Medicine, 8Az26A, 1953. 109 10. 11. 12. 13. 1A. 15. 16. 18. 19. 20. 110 Bouckaert, J. P., Capellen, L. and DieBlende, J. Muscle Mechanics. Journal of Physiology, 69: A73, 1930. Braunwald, E., Bloodwell, R. D., Goldberg, L. T., and Morrow, A. G. Studies on Digitalis IV. Observations in Man on the Effects of Digitalis Preparation on the Contractility of the Non— failing Heart and on Total Vascular Resistance. Journal of-Clinical Investigations, A0:52, 1961. Braunwald, N. 8., Gay, W. A., Jr., Morrow, A. G., and Braunwald, E. Slowing of Ventricular Rate and Augmentation of Contractile Force. American Journal of Cardiology, 1Az385-393, 196A. Burton,.A. C. The Importance of the Shape and Size of the Heart. American Heart Journal, 5A:801, 1957. Chardack, W. M., Gage, A. A., and Dean, D. C. Slowing of the Heart by Paired Pulse Pacemaking. American, Journal of Cardiology, 1A:37A-378, 1960. Cohn, A. E., and Levy, R. L. The Effect of Therapeudic Doses of Digitalis on the Contraction of Heart Muscle. Proceedings for the Society of Experimental Biology, (New York) 17:160, 1920. Cohn, L. J., Stein, W. G., Gadboys, H. L., Newman, B. J. Bloom, H. and Friedberg, C. K. The Effects of Rate, Exercise and Digitalis in DCgs with Complete Heart Block. Abstract. Clinical Research, 1A:2A2, 1966. Cotten, M. D. Circulatory Changes Affecting Measurement of Heart Contractile Force in Situations with Strain Gauge Arche. American Journal of Physiology, 17A: 365. 1953. Gotten, M. D. and Bay, E. Direct Measurements of Cardiac Contractile Force. Relationship of such Measurements to Stroke Work, Isometric Pressure Gradient and Other Parameters of Cardiac Function. American Journal of Physiology, 187:122, 1956. Cotten, Marion, D. and Maling, H. Relationships Among Stroke Work, Contractile Force and Fiber Length During Changes in Ventricular Function. American Journal of Physiology, 189(3)2580-586, 1957. Cotten, M. D. and Stopp, P. E. Action of Digitalis on the Non—failing Heart of the Dog. American Journal of Physiology, 192:11A, 1958. 21. 22. 23. 2A. 25. 26. 27. 29. 31. 30. 111 Cattell, M. and Gold, H. The Influence of Digitalis Glycosides on the Force of Contraction of Mammalian Cardiac Muscle. Journal of Pharmacology and Experimental Therapudics, 622116, 1938. Covell, J. W., Braunwald, E., Ross, J. Jr., and Sonnenblick, E. H. Increase of Myocardial Oxygen Consumption and Decrease of Myocardial Efficiency Produced by Digitalis Abstract. Clinical Research, lAz2A3, 1966. D (D Geest, H., Levy, M., and Zieski, H. Carotid Sinus Baroreceptor Reflex Effects upon Myocardial Contractility. Circulation Research, 151321, 196A. Fenn, W. 0., Brody, H., and Petrilli, A. The Tension Developed by Human Muscle at Different Velocities of Shortening. American Journal of Physiology, 97 l. 1931. Fenn, W. 0. Quantitative Comparison Between the Energy Liberated and the Work Performed by the Isolated Sartorious Muscle of the Frog. Journal of Physiology, 58:175. 1923. Fenn, W. 0., and Garvey, H. The Measurement of the Elasticity and Viscosity of Skeletal Muscle in Normal and Pathological Cases; a study of so- called ”Muscle Tonus.” Journal of Physiology, 58:A2l, 192A. Fenn, W. 0. Relation Between Work Performed and Energy Liberated in Muscle Contraction. Journal of Physiology, 58:373, 192A. Fenn, W. O. and Marsh, B. S. Muscular Force at Different Speeds of Shortening. Journal of Physiolog , 85:277, 1935. Frank, 0. On the Dynamics of Cardiac Muscle (C. B. Chapman, and E. Wasserman, trans). American Heart Journal, 58:282, 1959. Fry, D. L., D. M. Griggs, and Greenfield, J. 0., Jr. Myocardial Mechanics: TenSiOH-Velocity Length Relationship of Heart Muscle. Circulation Research, lAz73, 196A. . Gasser, H. S., and Hill, A. V. The Dynamics of Muscular Contraction. Proceeding of the Royal Society of London Series B 962398, 192A. ___.__)__~___,5 32. 33- 3A. 35. 36. 37. 38. 39. A0. A1. A2. A3. AA. 112 Gilmore, J. P., Sarnoff, S. J., Mitchell, J. H. and Linden, R. Synchronicity of Ventricular Contraction: Observations Comparing Haemodynamic Effects of Atrial and Ventricular Pacing. British Heart Journal, 25:299, 1963. Gleason, W. L. and Braunwald, E. Studies on the First Derivative of the Ventricular Pressure Pulse in Man. Journal of Clinical Investigations, Al:80—9l, 1963. Hartree, W., and Hill, A. V. Relationship of Muscle Length to Heat Evolved. Phil. Trans. B., 210:153, 1920. Hefner, L. L., Sheffield, T. L., Cobbs, G. C., and Willem, Klip. Relation between Mural Force and Pressure in the Left Ventricle of the Dog. Circulation Research, 11:65A, 1962. Hill, A. V. The Position Occupied by the Production of Heat in the Chain of Processes Constituting a Muscular Contraction. Journal of Physiology, A2:l, 1911. Hill, A. V. The Heat Produced in Contracture and Muscular Tone. Journal of Physiology, A0:389, 1910. Hill, A. V. The Heat Production of Surviving Amphibian Muscles, During Rest, Activity and Rigor. Journal of Physiology, AA:A67, 1912. Hill, A. V. The Energy Degraded in the Recovery Processes of Stimulated Muscle. Journal of Physiology, A6z28, 1913. Hill, A. V. The Absolute Mechanical Efficiency of the Contraction of the Isolated Muscle. Journal of Physiology, 55:133, 1921. Hill, A. V. The Mechanical Efficiency of Muscle. Journal of Physiology, A61A35, 1913. Hill, A. V. The Heat Produced During the Relaxation of Muscle. Journal of Physiology. 53:1xviii, 1920. Hill, A. V., and Hartree, H. The Regulation of the Supply of Energy in Muscle Contraction. Journal of Physiology, 55:133, 1921. Hill, A. V. The "Tension~Time" Production of Muscles. Journal of Physiology, 5Azliii, 1920-1921. A5. A6. A7. A8. A9. 50. 51. 52. 53. 5A. 55. 56. 113 Hill. A. V. The Maximum Work and Mechanical Efficiency of Human Muscle and Their Most Economical Speed. Journal of Physiology, 56:19, 1922. Hill, A. V. The Heat of Shortening and the Dynamic Constants of Muscle. Proceedings of the Royal Society of London. Series B., 126:136, 1938. Hill, A. V. The Transition from Rest to Full Activity in Muscle; the Velocity of Shortening. Proceedings of the Royal Society of London. Series B., 138:329, 1951. : Hill, A. V. The Heat of Activation and the Heat of Shortening in a Muscle Twitch. Proceedings of the Roygl Society of London. Series B., 1A1:10A, 1950. Katz, B. The Relation Between Force and Speed in Muscle Contraction. Journal of Physiology, 96:A5, 1939. Kavaler, F., and Morad, Martin. Paradoxical Effects of Epinephrine on ExcitationsContraction Coupling in Cardiac Muscle. Circulation Research, 182A92, 1966. Lefer, A. M., and Sutfin, D. 0. Cardiovascular effects of Catecholamines in Experimental Adrenal Insufficiences. American Journal of Physiology, 206:1151, 196A. Leight, L., Roush, G., Rafi, E., and McGaff, C. J. The Effect of Intravenous Potassium on Myocardial Contractility and Cardiac Dynamics. American Journal of Cardiology, 12:686, 1963. Levin, A., and Wyman, J. The Viscous Elastic Properties of Muscle. Proceedings of the RoyalSOCietycd‘London, Series B, 101:218: 1927. ’7 Levy, M. N., Elias, S. I., Zieske, H. Ventricular Response to Increased Outflow Resistance in Absence of Elevated Intraventricular End-Diastolic Pressure. Circulation Research, 12:107, 1963. Mallos, A. J. An Electrical Caliper for Continuous Measurement of Relative Displacement. Journal of Applied Physiology, 17:131, 1962. Mason, D. T., and Braunwald. Effects of Ouabain on the Non Failing Human Heart. Journal of Clinical Investigation, A2:1105, 1963. 57- 58. 59. 60. 61. 62. 63. 6A. 65. 66. 67. 11A Mommaerts, W. F. H. M. Energetics of Muscle Contraction. p. A3-A7, In Muscle, Edited by Paul, W. M., Daniel, E. E., Kay, 0. M. and Monckton, B. Pergamon Press Oxford, 1965. Niedergerke, R. The "Staircase" Phenomenon and the Action of Calcium on the Heart. Journal of Physiology of London, 13Az569, 1956. Patterson, S. W., Piper, H., and Starling, E. H. The Regulation of the Heart Beat. Jgurnal of Physiology (London), A8:A65, 191A. Perry, S. V. Muscle Proteins in Contraction. p. 29-A2, in Muscle, Edited by Paul, W. M., Daniel, E. E., Kay, 0. M., and Monckton, B. Pergamon Press Oxford, 1965. Podolsky, R. J. Mechanochemical Basic of Muscular Contraction Federation Proceedings, 21:supp1. 96A, 1962. Priola, D. V., and Pandall, W. C. Alterations in Cardiac Synchrony Induced by the Cardiac Sympathetic Nerves. Circulation Research, 15:A63, 196A. Reeves, T. J., Hefner, L. L., Jones, W. B., Coghlan, C. C., Prieto, G., and Carroll, J. The Hemodynamic Determinants of the Rate of Change in Pressure in the Left Ventricle during Isometric Contraction. American Heart Journal, 60:7A5, 1960. Reeves, T. J., and Hefner, L. L. Isometric Contraction and Contractility in the Intact Mammalian Ventricle. American Heart Journal, 6Az525, 1962. Remington, J. W. Introduction to Muscle Mechanics, with a Glossary of Terms. Federation Proceedings, 21:95A, 1962. Ritchie, J. M., and Wilkie, D. R. The Dynamics of Muscular Contraction. Journal of Physiology, 1A3: 10A, 1958. Ross, J. Jr., Braunwald, E., and WaldHausen, J. A. Studies on Digitalis II. Extracardiac Effects on Venous Return and on the Capacity of the Peripheral Vascular Bed. Journal of Clinical Investigations, 39:937. 1960. 68. 69. 70. 71. 72. 73. 7A. 75. 76. 77. 78. 79. 115 Ross, J. Jr., Waldhausen, J. A., and Braunwlad, E. Studies on Digitalis 1. Direct Effect on Peripheral Vascular Resistance. Journal of Clinical Investigations. 39:930, 1960. Rushmer, R. F., Crystal, D. K., and Wagner, C. The Functional Anatomy of Ventricular Contraction. Circulation Research, I;162, 1953. Rushmer, R. F. Continuous Measurements-of Left' Ventricular Dimensions in Intact, Unanesthetized Doss. Circulation Research, 2:1A, 195A. Rushmer, R. F. Length-Circumference Relations of the Left Ventricle. Circulation Research, 3:639, 1955. Rushmer, R. F. Anatomy and Physiology of Ventricular Function. Physiology Review, 36:A00, 1956. Rushmer, R. F. Initial Phase of Ventricular Systole: Asynchronous Contraction. American Journal of Physiology, 18Azl88, 1956. Rushmer, R. F., Smith, 0., and Franklin, D. Mechanisms of Cardiac Control in Exercise. Circulation Research, Rushmer, R. F., and Thal, N. The Mechanics of Ventricular Contraction: A Cinefluorographic Study. Circulation, A:219, 1951. Sandow, A. In Biophysics of Physiological and Pharmacological Actions, Edited by Shanes, AIM., Washington, D. 0.: American Association of Advanced Science, p. A13, 1961. Sarnoff, S. F., and Mitchell, J. H. The Regulation of the Performance of the Heart. American Journal of Medicine, 30:7A7, 1961. Sarnoff, S. J., and Mitchell, J. H. Regulation of the Performance of the Heart. In Handbook of Physiology section 2. Circulation. Edited by W. F. Hamilton, and P. Dow. Washington, D. 0.: American Physiology Society, l:A89—532, 1963. Siegel, J. H., and Sonnenblick, E. H., Judge, P., and Wilson, W. S. The Quantification of Myocardial Contractility in Dog and Man. Cardiologia, A5:189, 196A. 80. 81. 82. 83. 8A. 85. 86. 87. 88. 89. 90. 116 Siegel, J. H., and Sonnenblick, E. H. Isometric Time—Tension Relationship as an Index of Myocardial Contractility. Circulation Research, 12:597, 1963. H Sjostrand, F. S. Ultrastructural Changes in Skeletal Muscle Myofibrils in Connection with Contraction. Nature, 201:A5, 196A. Sonnenblick, E. J., and McCallum, A. T. Active State, Force Velocity Relationships, Inotropic Mechanisms, in Mammalian Papillary Muscle. Federation Proceedings, 20:126, 1961. Sonnenblick, E. H. Force Velocity Relations in Mannalian Heart Muscle. American Journal of Physiology, 202:931, 1962. Sonnenblick, E. H. Implications of Muscle Mechanics in the Heart. Federation Proceedings, 2l:supp1., 975, 1962. Sonnenblick, E. H., Blick, G., Morrow, A. G., and Braunwald, E. Force-Velocity Relations in the Human Heart. Journal of Clinical Investigations, A3zl2A5, 196A. Sonnenblick, E. H. Instantaneous Force-Velocity Length Determinants in the Contraction of Heart Muscle. Circulation Research, l6:AA1, 1965. Sonnenblick, E. H. Determinants of Active State in Heart Muscle: Force, Velocity, Instantaneous Muscle Length, Time. Federation Proceedings, 2Azl396, 1965. Sonnenblick, E. H., Williams, J. F., Glick, Gerald, Mason, D. T., and Braunwald, E. Effects of Cardiac Glycosides on Myocardial Force-Velocity Relations in the Nonfailing Human Heart. Circulation, 3Az532, 1966. Tolman, R. A., and Young, P. G. Slope Changes of the Ventricular Pressure Curves Compared with Ventricular Function Curves. Federation Proceedingg, 20:12A, 1961. Veragut, U. P., and Krayenbfinl, H. P. Estimation and Quantification of Myocardial Contractility in the Closed-chest Dog. Cardiolggig, A7z96, 1965. 91. 92. 93. 9A. 95. 96. 97. 98. 99. 100. 101. 117 Wallace, A. G., Skinner, N. 8., Jr., and Mitchell, J. H. Hemodynamic Determinations of the Maximal Rate of Rise of Left Ventricular Pressure. American Journal of Physiology, 205:30, 1963. Walton, R. P., Cotten, M. D., Brill, H. H., and Gazes, P. 0. Factors Influencing Measurements of Contractile Force of Heart Muscle £2 Situ. American Journal of Physiology, 161:A89, 1950. Walton, R. P., Leary, J. S., and Jones, H. P. Comparative Increase in Ventricular Contractile Force Produced by Several Cardiac Glycosides. Journal of Pharmacological Exporimental Therapeudics, 98: 3A6, 1950. Weissler, A. M., Gamel, W. G., Grode, H. E., Cohen, S and Schoenfeld, C. D. The Effect of Digitalis on Ventricular Ejection in Normal Human SubjeCts. Circulation, 29:721, 196A. ‘ 3 Wiggers, C. J. Some Factors Controlling the Shape of the Pressure Curve in the Right Ventricle. American Journal of Physiology, 33:382, 191A. Wiggers, C. J. The Mechanism of Cardiac Stimulation by Epinephrine. Journal of Pharmacological Experimental Therapeudics, 30:233, 1927. Wiggers, C. J. Are Ventricular Conduction Changes of Importance in the Dynamics of Ventricular Contraction? American Journal of Physiology, 80:12, 1927. Wiggers, C. J. Studies on the Cardiodynamic Actions of Drugs. 1. The Application of the Optical Methods of Pressure Registration in the Study of Cardiac Stimulants and Depressants. Journal of Pharmacological Experimental Thergpeudics, 30:217, 1927. Wiggers, C. J., and Stimson, B. Studies on the Cardiodynamics Actions of Drugs. 111. The Mechanism of Cardiac Stimulation by Digitalis and G-strophanthin. Journal of Pharmacological Experimental Therapeudics, 30:251, 1927. ‘ Wiggers, C. J. Dynamics of Ventricular Contraction Under Abnormal Conditions. Circulation,5:321, 1952. Wiggers, C. J. Studies on the Cardiodynamics Action of Drugs. II. The Mechanism of Cardiac Stimulation bK Epinephrine J Ph rmacolo ical, Experimental T erapeudics, 30:233, 19 . " APPENDICES 118 APPENDIX A 119 STEPWISE CONSTRUCTION OF STRAIN GAGE TRANSDUCER USED TO MEASURE THE MYOCARDIAL CONTRACTILE FORCE* Shim Stock Preparation 1. Cut the 2.5% beryllium COpper sheeting, into A mm. x 12 mm. using a large paper cutter— 2. Flatten all edges, using scalple handle and a hard surface. 3. Drill four small holes in each corner of the metal shim (a dental drill with a #30 drill); A. The metal shim is then molded into the form of an arch, using a cylindrical iron pipe with a piece of metal, of the same curvature as the cylindrical pipe. The metal shim is placed between the pipe and metal and clamped in a Vice. 5. The arched shims are then placed in a muffle furnace for two hours at 6000 F. Quench immediately afterwards in cold water. 6. When cool, remove all sharp edges with a file. 7. Soak filed arches in metal conditioner for approximately one half hour with frequent shaking. 8. Sand the metal shim with Silicon Carbide (180 Grit) until shim is free of any imperfections. 9. Rinse sanded shims in isopropyl alcohol to degrease. Store. Shim is now ready for bonding. §Erain Gage Preparation 1. The entire strain gage is covered with mylar tape. 2. The strain gage is then taped to a solid surface and the epoxy backing is trimmed away from the edges using a new razor blade. *Transducer construction published by: Reinke, D. A., Rosenbaum, A. H. and Bennett, D. R. Patterns of Dog Gastroin— testinal Contractile Activity Monitored in Vivo with Extra- lumlnal Force Transducers. American Journal of Digestive Diseases 12:113 (1967). 120 3. A. 121 The back of the strain gage is cleaned, using a cotton tipped swab, with neutralizer. The strain gage is now ready for bonding. Bonding Procedure 1. The bonding material is GA—5 epoxy adhesive and activator. It is mixed according to directions provided. The activator and adhesive should be mixed thoroughly. However, care should be taken to keep the amount of bubbles in the solution to a minimum. A small drop of activated adhesive is placed on both surfaces of the metal shim.‘ Spread evenly Over the entire shim. . Place strain gages on both sides of the shim. Press the strain gage down firmly to remove all bubbles from under it. The shim and its two strain gages are than placed under pressure using two carefully placed Silastic rubber-aluminum p1ates,on both sides of the shinyheld together with two 1 1b. negator clamps. The package (plates, clamps, shim and gages) is placed in an oven and heated at 200—220° F. for one hour. Dismantle the package upon cooling and cut away excess cement, and remove mylar tape from upper surface of strain gage and soldering tabs. Soldering Procedure 1. The soldering tabs are cleaned with methyl ethyl Ketone and plumice to promote a better soldering surface. The teflon insulated ll—A wire (36 gauge, 3 conductor) is inserted into a solution of Tetra Eche to promote the bonding of the teflon to Silastic. After rinsing in water, the ends of the teflon insulated wire are stripped and tinned for 2.5 millimeters. 122. A small drop of solder, on the tip of the soldering iron is placed on each of the four soldering tabs. The teflon insulated wire is firmly held over the solder and with the iron, the attachment is made for three of the four tabs on the two strain gages. To complete the 1/2 wheat stone brigde, a small wire (7-A, #3A Soldi cu, one conductor, Soldereze insulated) is soldered from the solder tabe of the above strain gage to soldered tape of the lower strain gage. After soldering, the strain gage and wires are cleaned using rosin solvent. Another thin layer of activated GA—5 adhesive is applied to the upper surface of the strain gage, solder joints, and shim. Allow to air dry for 2A hours. After drying, a protective water coating material is applied to the surface of the transducer and teflon insulated wires. The water coating used was Gage Kote #2 (mixed 1:5 with melhylethylkeytone). Several layers should be appled. Encapsulation Procedure 1. Silastic tubing (Medical-Grade tubing .058" ID by .077” OD) is cut and cleaned with Ivory Flakes. The lead wires from the gages are coiled within the silastic tubing. The ends of the tubing containing the coiled wires are plugged or filled with G.—E. adhesive sealant (silicone rubber). Silastic sheeting (non—reinforced) is used to encapsulate both the transducer and a portion of the silastic tubing containing the lead wires. The Silastic sheets (2 x 2 cm. by .0A0 inch.) are cut and cleaned with Ivory Flakes detergent and rinsed in water. Medical Adhesive is generously applied to one surface of each piece of the cut silastic sheeting. There should be no bubbles. The transducer and 123 lead out tube is then sandwiched between the two pieces of silastic sheeting and held under pressure for at least 12 hours. After adhesive has dried, the transducer is trimmed using a razor. The gage is now ready for attachment to the Animal Sensor Plug. Construction of the Animal Sensor Plpg l. The animal sensor plug consist of a female cannon electric plug mounted in silastic sheeting. The procedure is to solder the free ends of the coiled lead wires, from the strain gage transducer, to the appropriate connectors of the cannon plug. The solder joints are cleaned with the rosin solvent and several coats of Gage-Kote (diluted 1:5) #2 is applied. The cannon plug connector are then bent perpendicular to the plug. Medical grade silastic sheeting (.080 inch.) is out such that it is larger than the bent cannon plug. A second pieCe of silastic is cut with a small hole, size of the female end of cannon plug, in the center. The silastic sheeting is cleaned with Ivory Flakes and a generous amount of medical adhesive is applied to one side of each of the cut pieces of silastic sheeting. The cannon plug and silastic tubing, containing the coiled lead wires, are sandwiched between the two silastic sheets and held for 12 hours or more under pressure. Construction of Receivihg_Coil From animal sensor plug to bridge box). 1. A piece of tygon tubing (l/2;'ID-10' long) is coiled around an iron pipe (1 1/2” OD) and placed in hot water overnight. After the tygon tubing is dried and removed from the iron pipe, it retains its shape—that of a spring coil. Four wires (15-B -3 conductor—Teflon insulated) are pulled through the tygon tube. 12A One end of the tubing,with the A wires is a attached (soldered) to a male cannon plug. This plug fits into the female animal sensor plug. The other end of the tygon coil leads to the wheatstone bridge adaptor box which goes directly to the input of the grass polygraph (circuitry of input bridge 2K). APPENDIX B 125 LIST OF MATERIALS Metal for Shim Stock Cement 2.5% beryllium copper sheeting, .00A and .008 inch thick in the ”quarter-hard” state. Meier Brass and Aluminum Co., lA71 E. 9 Mile Rd., Hazel Park, Michigan. Lead Wire #36 gauge stranded COpper wire, three conductor, Teflon insulated, Code no. ll—A. #3A gauge solid copper wire, 1 conductor, solderize insulated, Code no. 7—A. #3A gauge solid copper wire, 3 conductor, Teflon insulated, Code no. l5—B. William T. Bean, 18915 Grand River Ave., Detroit 23, Michigan. Waterproofing Gagekote #2, nitrile rubber solution. William T. Bean, Detroit 23, Michigan. Cement GA—5 Epoxy Cement. Instruments Division, Budd Co., PhoeniXVille’ Pennsylvania. Soldering Accessories Strain gage solder, 3000 F., .015 inch diameter American Beauty Soldering Iron #B—2000 w/B—3 tlps. William T. Bean, Detroit 23, Michigan. 126 127 Accessories for Cleaning Metal Sheeting and Bonding Neutralizer 2 oz. BtLS Cotton applicator—Pg. of 100 Pumice 1/2 oz. Jar Code 7—A Wire 100” roll Cellophane tape 3/A” x A00" rolls Silicon carbide (180 grit) pkg. of 12 Metal conditioner 2 oz. bottle Rosin solvent 1/2 oz. bottle Silicon Carbide (800 grit) Tetra—etch 2 oz. bottle N/A, 1 lb. Neg—Ator Clamp N/A, 300° F. Strain Gage Solder Lot N/A, Mylar Tape, 1/2” x 200” Roll Metal Conditioner, 1 qt. Gage Kite 32 1 kit of 12 oz. btl. Teflon Sheet (.003 x 2 x 60”) William T. Bean, Detroit 23, Michigan Strain Gages Gage type MD—DV—090 DG—350 Gage type SA—09—090 DH—350 (epoxy on both sides of gage). William T. Bean, Detroit 23, Michigan Tube Fillop G. E. 113 RTV Silicone Rubber Silicone Products Department, General Electric Company, Waterford, New York 12188. Adhesive Dore Adhesive and Catalyst 2 lbs. John L. Dore Co., 5A06 Schuler, P. O. Box 7772, Houston 7, Texas. Cannon Plug MD 1—15SL 1 Electrical Connector (female) 051A03—0001 128 MD1—15PLI Electrical Connector (male) 051402—0001 Newark Ferguson, 20700 Hubbell Ave., Detroit, Michigan A8237. Needles and Sutures Double Needle 000 Merisilene suture Ethicon, Inc., Sommerville, New Jersey. Silicone Rubber Tubing 3H5—10610 Silicone Rubber Tubing .058" I.D. X .077” O.D. 10' coil 3H5 10618 Silicone Rubber Tubing .132" I.E. X .183 O.D. 10' coil V. Mueller and Company, 330 S. Honore St., Chicago, Illinois 60612. Silastic Sheeting Medical Adhesive Type A (Silicone) 1 two oz. Tube Silastic Brand Sheeting (Med. Grade) 1 pk. Nonreinforced .0A0" 1 pk. Nonreinforced .080” (Extra Firm Grade) 1 pk. Reinforced .OAO” V. Mueller and Company, 330 S. Honore St., Chicago, Illinois 60612. APPENDIX C 129 CHRONIC EXPERIMENT Purpose It was one of the objectives of this thesis to study cardiac contractile force of the dog in his undisturbed cage environment. This chronic experimental data was to be compared to the acute anesthetized dog data. However, because of various complications only partial success was achieved on the chronic dog preparations. Presurgery Conditioning of Dogo The dogs had been conditioned to their cages (in which recordings took place) for approximately six months before surgery. Four weeks before surgery,ropes hanging from the tops of the cages were tied to the dogs in harness each evening. This conditioning accustomed each dog to the plug— in coil which was used for collecting force data post- surgery. All data collections were recorded in an adjacent room such that the dog did not experience any distraction during the procedure. Methods In five healthy dogs (beagles) under sterile conditiona the following was performed: After aneSthetizatiOn(sodium pentobarbital 30 mg./kg.), clipping and intubation, two incisions were made. The first was between the scapulae for 130 131 implantation of an animal sensor plug and the second was in the right Ath. intercostal space. The right lung was packed down with wet gauze pads for better exposure of the right heart. The right ventricle was exposed by a three inch incision in the pericardium. The transducer and its cable were inserted under the skin, with the aid of a troca, from the incision between the two scapulae to the rib incision. The skin was then sutured around the animal sensor plug (button) leaving exposed only the female connectors of the button. The strain gage transducer was next sutured firmly to the right ventricle. Two ECG electrodes were sutured under the skin on each side of the 6 chest. The incisions were closed and penicillin (10 units/ day) was administered up to four days postsurgery. . Results Three days postsurgery four out of five dogs gave good right heart contractile force recordings. The ECG recordings from the dogs were very noisy because of difficulties in N grounding the animals in their cages. Five days postsurgery only one of the five strain gage transducers gave good heart force recordings. The seventh day post—surgery the remaining gage also detected large interferences. After post mortem on each dog it was discovered that the cause of the poor contractile force recordings was adhesions in the chest. Between four and five days post— surgery, when the strain gage transducer produced many 132 abnormal recordings, adhesions had formed around the gage, between the gage and the pericardium. In many instances these were connected to the lungs and in two cases to the diaphram thus making the force recordings impossible to interpret. However, some significant data were obtained before severe adhesions had developed, that is, three days post- surgery. In comparing the contractile force recordings of the dog in the supine position to that of the standing position, it was noticed that in all four dogs tested, a definite arrhythmia occurred in thesupine position. When the dog stands, this arrhythmia immediately disappears (Figure 23). Each day after surgery the right heart contractile force was found to be less than that recorded the previous day. For example, immediately post-surgery, (closed chest, anesthetized) the cardiac peak systolic force was approximately 50 grams. The first day after the operation, unanesthetized dog, the peak force was A0 grams and the second day 35 grams and the fifth day it declined to 25 grams. The response of the unanesthetized dog to 2.5 ug epinephrine as compared to the anesthetized open—chest animal is shown in (Figures 23). The results suggest that the percent change in cardiac force in response to 2.5 ug epinephrine in the unanesthetized dog is less than in the acute preparation. Figure 23. A.—-Changes in the contractile force in response to 2.5 ug. epinephrine. Closed chest, unanesthetized dog. From above downwards, control force as recorded from the strain gage transducer (S.G.T) and the simultaneous recording of the first derivative (df/dt). The rise in force and the simultaneous recording of the first derivative (df/dt) in response to 2.5 ug. epinephrine. B.——Changes in the contractile force in response to 2.5 ug. epinephrine. Open chest, anesthetized dog. recorded at a speed of 5 mm./sec. From above downwards, force as recorded from the strain gage transducer (S-G-T')’ and the simultaneous recording of the first derivative (df/dt) of the force tracings. C.——Changes in the heart rhythm of the closed chest unanesthetized dog, as observed by the force recordings from the strain gage transducer. Reocrder at a speed of 5 mm./sec. 5—1: on . :3 (l) A W 1 IT“ J'I-‘IQQ I u WC III‘vS' ‘1‘: (1’ Q It. 13A Contractile J Force , #0 gm. _ i JIII‘LIIIJIIIIIIJIJIIUIUJIMJJILUI Standinu Supine “Row. 24 0 Contractile Force Control df.dt 722m. 4 24 O Contractile Force 2.5 ug. Epinephrine I I II " ' II l —-———— Contractile Force T“ 'I »! (If I'! I II! t , 135 There was no significant response or change in contractile force in the unanesthetized dog due to 0.7 mg. (I.V.) ouabain, with the exception that the dog regurgitated on the investigator. Discussion and Conclusions It is possible that better surgical techniques would eliminate some of the adhesions between the heart, gage, pericardium, lungs and diaphram of the dog, and permit better heart contractile force recordings (S.G.T.). However, another investigator (17) has reported similar adhesion problems in the chronic dog preparation. The fall in the peak cardiac force each days after surgery is probably caused by a gradual loosening of the attachments of the gage to the myocardium and/or possibly because of the interference due to adhesions around the gage itself. The response of the heart to 2.5 ug epinephrine in the unanesthetized dog was noticably smaller as compared to the open chest anesthetized dog (Figure 23). The reason for this is probably the adhesions. In conclusion the author suggest that by overcoming the problems of adhesion, possibly by better surgical techniques, (or by any other means) the strain gage transducer should provide a technique whereby the heart muscle can be studied directly in chronic dog preparations for long peTiOdS 0f time. 136 Figure 2A.—-Circuitry for coupling the strain gage transducer to the Grass amphifiers. 137 .440 O... O (r mHuw _ _ .5020 $ _ r... A wz Honpcoo mU:oo-- . - ,4 4 amMHHH? \» > >._- KL: PH HHH HH H .._. > > >H PH ‘1 g A owwh mmoo whammwpa «o mums HmEwaE mno ocm m>m3um m - , noom so xmwa mgp cowzuop Hm>smucfl mEHB IUQWLWM so Mama stflxme mnu Ucm w mmfig xmw ozo gm);pw >m21m 1 a: n Hm>ampcfl o - ETB *.mmwp 00909 cm mpsm 4- u ecu cmwzpwp mam>mwucH o a» pr o wwha ac wows HwwamE mo zowcoa on» :0 cospmamccw Emoso 4 0. (MN (I J.- 145 Table 9.——The effects of chloroform inhalation on the force and pressure df/dt maximum and dp/dt maximum respectively.* Pressure at dp/dt maximum Force at df/dt maximum 95%5 IV IV IV V V III IV IV IV V V Control Value Millimeters of Hg. Grams 8.1 4.2 3.3 3.3 4.2 4.2 12 15 14 14 12 13 8.7 3.6 3.6 3.0 3.9 4.2 13 17 13 13 14 14 7.8 3.6 3.6 3.0 3.9 4.2 14 16 1A 12 12 1A 8.4 4.2 3.6 3.6 4.2 4.8 12 15 13 14 13 15 7.5 4.5 3.0 3.3 3.9 4.2 13 16 13 13 12 15 8.4 4.2 3.3 -—- ——- ——— 13 18 14 —— —— —- -—- 4.5 3.3 —— —— —- —- 17 13 —— -— —- __ __ -_ __ __ __ -_ 16 _- __ __ __ During Chloroform Inhalation 7.8 4.2 3.3 3.0 3.9 3.9 13 16 16 13 12 13 7.5 4.5 3.6 3.3 3.6 3.6 13 16 14 13 14 13 7.2 4.2 3.3 3.0 3.6 3.3 13 18 14 14 12 13 8.1 4.2 3.3 3.3 3.3 3.6 12 16 14 13 12 12 6.9 4.2 3.3 3.3 3.0 2.6 12 16 17 13 10 11 6.6 3.6 3.0 3.0 2.8 2.6 14 15 13 14 10 11 7.2 3.0 2.3 2.3 2.6 3.0 12 12 12 12 10 10 7.2 3.0 2.3 2.3 2.6 ——- 13 13 12 13 10 _— 7.8 2.4 2.0 2.0 ~—— ——— 14 13 12 12 —— —— 7.5 3.0 1.6 2.3 ——— —-- 14 12 12 12 —— _— 7.5 2.6 1.6 2.3 ——— ——— 15 12 11 11 —— ~— 7.2 ——— 2.3 2.0 —-— ——— 15 —— 12 10 _— _— 7.1 -—— 1.6 1.6 -—— —-— 16 —— 11 10 —— _— 7.8 ——— ——— 1.3 ___ ——— 1A —— —— —— —— _— 7.2 ——— ___ ___ ___ ___ 18 __ __ __ _- __ 6.7 ——- ___ ___ ___ ___ 15 __ __ __ __ __ 6.6 ___ ___ ___ ___ ___ 1A __ __ __ __ __ 6.4 ___ ___ ___ ___ ___ 1A __ __ __ __ _— 6.3 ___ ___ ___ ___ ___ IA __ —— —— —— _— 6.6 ___ ___ ___ ___ ___ 1A -_ __ __ __ _— 6.0 ___ ___ ___ ___ ___ IA —— —— —— __ _— 6.9 ___ ___ ___ ___ ___ 1A __ __ __ __ _— 6.3 ——— _-_ ___ ___ ___ IA —— _— —— —- _— 6.0 ___ -_~ ___ ___ ___ 1A __ __ __ __ _— 6.6 ___ ___ ___ ___ ___ 13 __ —_ __ _- _— *Same as Table 6. 146 Table 10.——The effects of epinephrine on the maximal rate of pressure rise (dp/dt) and the maximal rate of force rise (df/dt) in the dog right heart.* df/dt maximum dp/dt maximum gm/sec. mm. Hg./sec. Control Values Dggs VI V VI V VI V VI V VI V VI 1.25 ug. 2.5 ug. 5.0 ug. 1.25 ug. 2.5 ug. 5.0 ug. 60 57 7O 57 7O 60 105 75 80 7O 55 70 65 60 75 57 72 60 100 70 80 70 55 75 65 6o 70 60 70 65 110 70 80 75 57 75 65 57 70 57 70 6O 110 75 82 75 57 75 70 60 70 57 70 60 110 72 80 77 57 75 67 —_ 70 ___ 70 ___ 100 ——— 80 ——— 55 —-- 70 _— 70 --- 65 ——— 120 ___ 80 ___ 55 __— _- __ ___ ___ 7O ___ ___ ___ ___. ___ ___ ___ Following Epinephrine Injection 77 70 85 95 100 115 120 90 87 100 60 112 80 80 97 110 160 1A5 120 97 105 135 90 170 75 80 105 110 170 135 115 100 120 1A0 160 125 77 75 110 100 165 110 125 90 132 120 160 1A2 8O —- 115 ——— 170 135 120 ——— 137 ——— 165 __— 80 —— 115 ——— 160 110 120 ——— 140 ——— 150 ——— 82 —- 110 ——~ 155 110 140 ——— 135 ___ 155 __— 90 -— 110 ——— 1A0 ——- 140 ___ 130 ___ 1A5 __— 85 -— -—— ___ 130 ——— 140 ___ 130 ~-- ___ __— 80 —_ ___ ___ ___ ___ 130 ___ ___ ___ ___ ___ 85 —— ——— ___ ___ ——— 140 ——- ——— ——— ——— ——— 95 _— ___ ___ ___ _-_ 140 ___ ___ ___ ___ __— 85 —— ___ ___ ___ ___ 160 ___ ——- ——— -—— __— 90 —_ ___ ___ ___ ___ 140 ___ ___ ——- ___ __— 90 _— ___ _-_ ___ ___ 150 ___ ___ -_— ___ ___ 90 —— ——— -__ ___ ___ 135 —-— ——— ——— ——— ——— 85 —_ ___ ___ ___ -__ 150 ___ ——— ___ ——— __— 90 __ ___ __- __- ___ 160 ___ ___ ___ ___ __— 85 -— ——— ——— ——— -—— 16o ——— ——— ___ ——— ___ 9o _— ___ ___ ___ ___ 150 ___ ___ __— ___ ___ 85 —— ___ ___ ___ ___ 160 ——— ___ ___ ___ __- 85 —— ___ ___ ___ __— 180 ——— ——- ___ ___ __— 90 —— ——- ——— ___ ——— 160 ——— ——— ——— ——— ——- 90 —_ -—— ___ _—- ___ 150 ___ -—— _—_ ——— __— 90 —— ——— ——— ——— ——— 16o ——- ——— ——— ——— —-— —— —— ——— ——— ——— —-— 140 ——— ——— ——— ——— ——— 150 147 Table 11.——The effects of epinephrine on the duration of the time interval between the peak of the ECG-R—wave to the development of the maximal rate of force (df/dt) and pressure (dp/dt) rise in the dog right heart.* Time Interval (msec.) Time Interva1(msec.) Control Values Dffis II III III IV IV II II III III IV IV 1.25 ug. 2.5 ug. 5.0 ug. 1.25 ug. 2.5 ug. 5.0 ug. 55 77 55 82 55 80 85 77 80 75 80 85 80 82 77 82 75 80 82 55 77 -- 82 55 80 55 —- 85 77 -— 77 —- 77 55 80 —— —— 85 77 —— 80 82 _— -— 77 57 80 -- -— —— —— —— 75 82 __ -— 80 55 —— _— —— __ __ __ 77 __ __ 52 77 45 —— 55 75 A5 57 A0 70 65 65 50 72 A2 _— 52 75 45 —- A2 67 55 65 55 7O 45 —— 52 70 A7 60 A5 67 55 65 50 70 A5 67 50 72 A5 57 A7 67 60 65 60 67 37 67 50 70 A7 60 A5 67 75 67 65 70 A2 67 52 72 —_ —— 50 65 75 70 —— 70 50 67 55 72 —— 62 A7 65 75 70 —— 70 55 _— 55 72 —— 60 —— 65 —— 70 —— 70 60 70 -- 72 —— 60 —— 67 —— 72 —— 72 —- 70 -— 72 -— 65 —— —— —— -— —— —- —— 65 __ 7o __ __ __ __ __ -_ __ __ __ __ *Same as Table 6. 148 w mHDdB mm wEdm* HM... a... um um HM HM ma $2 2 .1 .3 mm.m mm.: -- mo.m -- -- 3H.m mH.: so.m om.o ma.fi -- m.: -- -- oH.: mama so.m om.m om.: -- ms.m mm.m -- om.m oo.: 5o.m om.m mo.a -- m.: mm.H -- oa.z a: H oo.m mm.m mo.: -- H:.m ss.m m:.m ma.m oo.m ms.m oo.o mo.fl -- m.m oo.H mm.m m3.1N om.H ms.m oo.m :s.m :o.m mm.m so.m s:.m Ho.m oo.m m..m oo.o so.A so.m m.: mm.H mm.w mo.: s2.H ms.m wo.m so.m oo.m ms.m os.m :o.m mo.m s:.m m.m sm.z oo.fi :o.m m.: m:.H m:.m Hm.: sm.H mo.m Ho.m mm.m mo.m mo.m :o.m sm.m sm.m :s.m om.m mm.m mq.fl oo.m m.: mm.fi o:.m mm.m Hm.H ms.m ms.w ::.m mm.m ms.m mo.m os.m ms.m m:.m om.m Hm.m m:.H wo.m 0.: Hm.H mm.m ma;N Hm.H mm.m ws.w so.m mm.m :m.m :o.m o:.m mo.m s:.m ofi.m mo.m Ho.H HH.m m.m mm.a wcfiscgmcflom mcfizosfiom -------- -- -n- -- -- sN.H -- -- ao.: ow.fl -- m.m . -- . -- -- mm mm A H a mo.: H> > >H . A.w3 o.mv . >H H> mummmm-wmmmmm- A we m.wo A.w= mms sH A.oom .wm .EEV 0 av mwoo whammmpm mo ngmoch oEHB - A.0mw\.smv otsom so HmnwouCH mafia NH wands .o oHomE mm oEmm* I'll. IIII III-I m . ml... lull «III II' .III IIII IIII IIII N . WH III III III III IIII .IIII N. . 3H III. III. III III III IIII IIII IIII MW .m-m III III III m.mH H.mm IIII m.sH IIII :.mH w m m.sH o.Hm o.wa m.sH o.sH m.HH m m m.mH m.mH o.mH o.mH m.wH o.HH w.s s m o z o l I rquficna-chmnn ”Hnoqunam::r:- :- o u o s.:H m.ma 0.:H w.mH m.ma m.HH Q.MH m.ma m.ma ©.NH o.ma m.HH o 149 COHpooncH ocflhnaocfigm wsflzoaaom m.ma m.:H z.MH w.mH m.ma w.OH m.m m.m s.m o.m w.m m.m E > E > E > E > E s. E. > ill-ll A.wm .EEV mosfio> Hoapcoo A.meV ESEflme po\go pm ohzmmoam ESEwaE po\so pm oopom *.Essflme po\oo pm thmmonQ mop Ugo ESEflNmE po\so pm wohom mop co osfihsgoCflQm so mpoomso oQBII.MH oHQmB 150 Table l4.—-The effects of ouabain on the maximal rate of pressure rise (dp/dt) and the maximal rate of force rise (df/dt) in the dog right heart.* df/dt maximum dp/dt maximum gm./sec. mm. Hg./sec. ' Control Values 85 125 ‘ 102 120 100 70 125 95 155 95 ___ —-— 105 125 97 —— —-— 100 145 97 ——— ——- ——— 120 100 -— ——— ___ 1A0 95 -—— -—— ——— 120 100 —— ——— ___ 1A0 90 —-- -—— —-- 115 105 —- —-- ——— 135 95 ——- ——— ——— ___ 100 —— ——— ___ ——— 105 ——— --— -—- ___ 110 -- ——— —-- ——— 100 Following Ouabain Injection 80 130 100 120 100 67 140 95 135 92 85 135 99 125 100 67 150 97 150 97 80 135 105 125 107 88 150 100 145 102 80 130 107 130 105 70 155 102 145 110 85 127 100 130 105 75 155 107 155 115 85 130 110 125 100 70 157 108 150 115 90 177 102 120 100 75 150 100 135 110 92 1A0 110 120 100 80 162 105 1A5 110 95 155 110 120 100 80 180 105 1A5 110 90 155 110 120 100 75 170 107 1A5 110 90 180 116 120 82 77 190 105 1A0 110 90 180 110 110 100 80 1A7 105 1A5 110 90 --— 120 115 100 70 ——— 110 1A0 115 95 ——- 110 130 100 75 —-— 105 1A0 115 90 ——— 120 115 95 80 ——- 108 1A0 115 , 110 120 100 80 ——— 107 1A0 115 96 ——- 112 120 100 70 ——— 107 1A0 110 90 --— 120 105 105 75 --— 107 1A5 110 95 -—- 125 115 100 80 ——— 110 1A0 110 100 ___ 120 115 105 80 ——- 115 1A5 110 100 ___ 120 115 110 75 ——— 120 150 110 95 -—— 127 115 100 80 ——- 120 1A5 110 95 ——— 135 120 105 80 ——- 120 1A5 110 100 —-- 125 120 110 85 -—— 118 1A5 110 5 ——— 128 120 107 75 -—— 118 1A0 110 100 ——— 135 120 110 80 ——— 115 1A5 110 100 ——— 130 120 95 80 —-— 118 165 105 103 ——— ——— 120 105 85 -—— ——— 170 105 100 ___ ___ 1A0 92 80 -—— —-- 165 105 ——— ——— 130 105 80 ——— —-— 165 105 105 -—— -—— 135 105 85 ——— ——— 170 100 105 ——- ——- 135 110 90 ——— -—- 180 105 100 ___ ___ 1A5 110 80 -—— -—— 170 105 100 ___ ___ 1A5 105 85 --— ——- 170 105 110 ——- —-— 150 110 90 ——— ——— 170 100 100 ___ ___ 150 105 77 ——- —-— 155 100 100 —-- —-— 135 105 85 —-— ——— 175 110 110 ___ ___ 135 105 —— —-— ——— 175 ——— 151 Table 15.——The effects of ouabain on the duration of the time interval between the peak of the ECG—R—wave to the development of the maximal rate of force (df/dt) and pressure (dp/dt) rise in the dog right heart.* Time Interval Time Interval (msec.) (msec.) Control Values Digs II III V VI I II III V VI 68 55 67 55 55 77 65 7O 55 52 6O 55 60 55 57 7O 7O 7O 55 55 70 52 57 57 55 75 75 72 57 55 67 55 62 55 57 77 75 72 55 52 67 52 67 55 57 77 77 72 5O 55 62 55 62 55 57 75 75 75 55 55 65 52 70 55 55 80 75 75 50 52 65 55 60 57 6O 75 77 75 5O 52 65 55 65 57 60 75 75 75 52 52 67 57 65 57 55 -- 77 —— 5O 55 70 55 65 55 57 —— 75 —— 52 —— —— 55 6O —— 57 —— 8O —— 52 —— —- 55 —- —— 6O —— 77 -— -— —— -- 55 —— —— 57 -- 77 -- -— ‘:= __ __ __ __ 6O __ 77 __ __ __ —— -- —— —— 57 —— 77 —— -— —— __ __ __ __ -_ __ 75 __ __ __ 65 55 57 57 57 77 75 75 52 50 70 55 6O 57 57 75 75 75 52 52 67 55 57 60 57 80 77 7O 50 52 65 55 62 57 55 75 75 72 55 52 65 55 65 55 55 72 75 72 50 52 65 52 62 55 55 75 77 7O 52 52 60 55 70 52 6O 75 77 70 52 52 60 57 6O 57 60 77 72 72 52 52 62 55 65 5O 57 73 77 72 52 55 72 65 67 52 60 75 75 70 50 5O 65 52 62 57 55 73 75 75 50 52 65 50 67 57 57 75 75 7O 50 52 65 52 67 55 55 77 75 72 5O 50 70 55 70 52 6O 77 7O 70 50 52 7O 52 67 57 57 75 —— 75 55 52 70 55 7O 57 6O 80 ~— 70 52 52 7O 50 70 55 60 77 —— 72 50 52 67 52 7O 55 57 77 -— 75 52 52 65 —— 7O 52 55 75 —— 72 50 52 65 —— 62 55 57 80 —— 70 55 55 7O —— 7O 57 57 77 -— 75 55 52 7O -— 65 55 6O 77 —— 75 55 55 70 —— 67 57 57 8O —- 75 50 55 65 —— 65 55 57 75 -— 75 50 50 67 —— 67 57 57 80 —— 75 55 55 67 —- 6O 55 55 77 —— 72 55 52 65 —- 65 57 57 77 —— 80 5O 55 70 —— 65 57 57 75 —— 75 50 55 70 __ 67 —- 57 80 —— 72 52 50 67 —— 65 —~ 60 75 —— 70 52 55 —— —- 7O —- 57 77 —— 75 5O 52 r —- —— —- —— —— —— 72. 50 _— *Same as Table 6. 152 Table l6.--The effects of ouabain on the time integral (area) of pressure and force measurements in the dog right heart.* Time Integral of Force Time Integral of Pressure (gm./sec.) (mm. Hg. sec ) Control Values D855 II III V_ VI I II III V VI 1.79 1 63 1.66 1.18 1 67 1.75 3.01 2.91 4.36 3 30 1.73 1.66 1.64 1.19 1 76 1.74 2.95 2.88 4.39 3 28 1.75 1 59 1.66 1.18 1 71 1 79 2.91 3.01 4.19 3 31 1.77 1 66 1.67 1.16 1 79 1.83 2.88 2.08 4.10 3 21 1.85 1 6O 1 66 1.19 1 75 1.98 2.86 2.88 4.59 3 14 1.75 ‘——-— -—-— 1.15 1 82 1.81 ———— ———— 4.29 3.14 ——-— ~——- ~——— 1.19 l 69 ———— —-—— ———— 4 26 3.34 ———— ———- ———— 1.19 1 82 ———— ———— -—-— 4 13 3.25 ——-— ———- ~——- 1.11 1 82 ———— ~——— ——-— 4 46 3 21 ———— —-—— ———— ———— 1 87 -——— -——— —-—— ———— 3.20 1.70 1.65 1.67 1.23 1.82 1.78 3.00 2.99 A.39 ~3:A1 1 70 1.67 1 60 1.23 1.91 1.73 3.1A 2.87 A.29 A.05 1.77 1.63 1.67 1.27 1.83 1.82 3.01 3.03 A.20 3.77 1.81 1.69 1.79 1.3A 1.91 1.8A 2.89 2.93 A.22 3.60 1.83 1.63 1.7A 1.27 1.83 1.96 3.05 2.93 A.29 3.5A 1.78 1.67 1.71 1.27 1.75 1.7A 3.01 3.01 A.23 3.67 1.85 1.73 1.76 1.27 1.78 1.73 3.01 2.89 A.03 3.76 1.82 1.75 1.90 1.23 1.91 1.69 3.16 2.91 A.13 3.91 1.97 1.78 1.81 1.27 1.99 1.7A 3.16 3.00 3.93 3.88 1.98 1.85 1.86 1.27 1.99 1.85 3.18 2.91 3.93 3.81 1.89 1.82 1.91 1.3A 1.92 1.62 3.1A 3.07 A.19 3.60 1.91 1.83 1.96 1.A3 1.91 1.70 3.0A 2.91 A.A6 3.73 1.91 1.91 2.07 1.A3 2.05 1.57 3.10 2.86 A.36 3.93 2.07 2.02 2.07 1.A7 2.76 1.87 3.20 2.88 A.A9 3.9A 1.99 1.99 1.96 1.A3 2.31 1.69 3.13 2.91 A.29 3.9A 2.02 2.29 2.02 1.51 2.31 1.61 3.80 2.88 A.29 A.33 2.02’ 2.32 2.07 1.59 2.23 1.67 3.16 2.75 A.A6 3.67 2.06 ———— 2.1A 1.59 2.39 1.58 —-—— 2.88 A.26 A.59 1.98 ———— 2.09 1.58 2.A7 1.60 ———— 2.80 A.26 A.06 2.13 ———— 2.16 1.68 2.55 1.61 ———— 2.82 A.16 A.22 2 12 ———— 2.08 1.66 2.5A 2.07 ———— 2.75 A.85 A.06 1 9A ———— 2.25 1.66 2.A0 1.5A ———— 2.86 A.62 A.A6 2.01 ———— 2.27 1.71 2.23 1.62 -——— 2.8A A.92 A.98 1.99 ———- 2.31 1.69 2.56 1.70 ___— 2.79 A.59 A.9A 2.09 ———— 2.39 2.03 2.5A 1.73 ———— 2.79 A.78 A.59 2.01 -——— 2.39 1.66 ——-— 1.56 ___- 2.7A A.62 ___- 2.01 ———— 2.A1 1.69 ———— 1.57 ———- 2.7A A.88 ——2_ 2.06 ———— 2.53 1.69 ———— 1.58 ———— 2.88 A.29 ___— 2.17 —-—— 2.85 1.67 ———— 1.96 ———— 2.86 A.62 ___— 2.07 ———— 2.72 1.68 ———— 1.5A ___- __—— A.69 _-_— 2.02 ———— 2.75 1.69 ———— 1.57 —-—— —-—— A.30 ___— 2.10 ———— 2.72 1.63 ———— 1.61 -——— ———_ A.98 ___- 2.19 -——— 2 63 1.72 _——— 1.70 ___— ———— A.78 ___— 2.17 ———- —-—— 2.48 ———- 1.57 -——— ———— 4.69 ———— 2.17 —-—— ———— 2.66 ———— 1.88 -——— ———— 4.46 ——-— 2 30 ___- ___- 2.59 ———— 1.96 —_—— ———— A.27 ___— 2 30 ___- ——__ 2.39 ———— 1.61 ———— ———— A.56 -——— ———— ___- ___- -—__ ___- 1.58 ———— —-—— ___- ___- ———— ___- __—_ ———— ———— 1.96 ———— ___- ———_ ___- ——-— —-—— ———— -——— ———— 1.53 ——-— ———— ——_— ——-— *Same as Table 6. 153 Table l7.--The effects of ouabain on the force at df/dt 5(- maximum and the pressure at dp/dt maXImum. Pressure at dp/dt maximum g H m m m u m .l X a m t d) /. fS dm g t(\ a e C r O F Control Values VI III II II III Dogs 20500050005 3433.“.232532 11111111111 2 2 _ _ RZGQoRXUQUOQUQo_ _ 1111111111521.1 . __._ _ _ __ ..__ _. __ _ _ u _— ._ __ _— 38418812987 ........... hwthrththS-IHU-S . 855329555. _ uuuuu3uu.u. _ Following_0uabain Injection OqucnononVOAUnuvl91OIUAUnoRJOAUnunoOAUanunononcOFDsDanvO_DnUnVO “ ..................................... 5u37uu201266760110321233232001200021_ 11111_l1111111.1111111111111111111I.1.11111111.11111111.1111111111. 818880111886 121111222211 00505057252977080707020700500220u “ n u “u ................................ 90909100099090900809910021021109_ _ _ _ _. 1 11 1.1111 11 .1 1.1 1 1:11111111111111 __ _ __ . ...................................... 8n/Qu7-OABQUOJOAHQURURC0AHQuo/ino/OooOzozonvo/Ooo090/0n9n60n9n80 11 1 1 11 1. 1 111 111 ooh-1488848425884418457118140818779-44317 ...................................... “55.-Dun.“- 5u555uu555-Uv 5nd- 5555556” 575514.55555 82588.4111825881882555825558 588885811“? ...................................... _ ................. _ _ _ _ _ . _ _ _ . _ _ _ _ _ _ . _ _ _— 55555u65u54555676_ 118752 08.4 18u028u7uhfi 3-427-6 708-4-4070 0U. 0637 ...................................... 55h.- S-U. 56-455u 56 5M655565556 565556 EKG/05.6665 *Same as Table 6. IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIII IHllWHIIHVIIIHIIIHHllHUNIIIHWIHIIIWIIIHIHIH ,