Pathophysiology of Congenital Heart Disease [Reprint 2020 ed.] 9780520336353

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U C L A

F O R U M

IN

M E D I C A L

VICTOR E . HALL,

S C I E N C E S

Editor

MARTHA BASCOPÉ-ESPADA, Assistant

Editor

LBOARD Forrest H. Adams

William P. Longmire, Jr.

Mary A. B . Brazier

H. W . Magoun

Carmine D . d e m e n t e

C. D. O'Malley

Louise M. Darling

Sidney Roberts

Morton I. Grossman

Emil L. Smith

Reidar F . Sognnaes

U N I V E R S I T Y

OF

C A L I F O R N I A ,

LOS

A N G E L E S

PATHOPHYSIOLOGY OF CONGENITAL HEART DISEASE

UCLA FORUM IN MEDICAL SCIENCES NUMBER 10

PATHOPHYSIOLOGY OF CONGENITAL HEART DISEASE

Proceedings of a Conference held July, 1967 Sponsored by the Division of Pediatric Cardiology, Department of Pediatrics, University of California, Los Angeles, School of Medicine and the American College of Cardiology

EDITORS

Forrest H. Adams, H. J. C. Swan and Victor E. Hall

UNIVERSITY

OF C A L I F O R N I A

PRESS

BERKELEY, LOS ANGELES AND LONDON 1970

CITATION

FORM

Adams, F. H., Swan, H. J. C., and Hall, V. E. (Eds.), Pathophysiology of Congenital Heart Disease. UCLA Forum Med. Sci. No. 10, Univ. of California Press, Los Angeles, 1970

University of California Press Berkeley and Los Angeles, California © 1970 by The Regents of the University of California Standard Book Number 520-01630-0 Library of Congress Catalog Number 69-16626 Printed in the United States of America

PARTICIPANTS IN THE CONFERENCE Chairman and Editor Division of Pediatric Cardiology UCLA School of Medicine Los Angeles, California 90024

F O R R E S T H . ADAMS,

H. J. C.

Co-Chairman and Co-Editor Department of Cardiology Cedars-Sinai Medical Center Los Angeles, California 90029 SWAN,

VICTOR E . H A L L , Co-Editor Division of Pediatric Cardiology and Brain Information Service UCLA School of Medicine Los Angeles, California 90024

NICHOLAS S . ASSALI

Departments of Obstetrics-Gynecology and Physiology UCLA School of Medicine Los Angeles, California 90024 A L L A N J . BRADY

The Los Angeles County Heart Association Research Laboratory and Department of Physiology UCLA School of Medicine Los Angeles, California 90024 E U G E N E BRAUNWALD *

Cardiology Branch, National Heart Institute National Institutes of Health Bethesda, Maryland 20014 ROBERT L . D E H A A N

Department of Embryology Carnegie Institution of Washington Baltimore, Maryland 21210

" Present affiliation: Department of Medicine, University of California, San Diego, School of Medicine, L a Jolla, California 9 2 0 3 7 .

DONALD T . DESILETS

Department of Radiology UCLA School of Medicine Los Angeles, California 90024 S . EVANS DOWNING

Department of Pathology Yale University School of Medicine New Haven, Connecticut 06510 GEORGE C . EMMANOUILIDES

Division of Pediatric Cardiology, UCLA School of Medicine and Department of Pediatric Cardiology and Neonatology Harbor General Hospital Torrance, California 90509 DEAN L . FRANKLIN

Biomedical Engineering, Scripps Clinic and Research Foundation and University of California, San Diego, School of Medicine La Jolla, California 92037 W I L L I A M F . FRIEDMAN*

National Heart Institute National Institutes of Health Bethesda, Maryland 20014 IRA H . GESSNER

Department of Pediatrics University of Florida College of Medicine Gainesville, Florida 32601 STANLEY J . GOLDBERG

Division of Pediatric Cardiology UCLA School of Medicine Los Angeles, California 90024 PAUL H . HEINTZEN

Universitäts-Kinderklinik University of Kiel 23 Kiel, West Germany PAUL G . HuGENHOLTzf

Children's Hospital Medical Center and Department of Pediatrics, Harvard Medical School Boston, Massachusetts 02115 * Present affiliation: Division of Pediatric Cardiology, University of California, San Diego, School of Medicine, L a Jolla, California 92037. f Present affiliation: Department of Cardiology, University Hospital, University of Rotterdam, Rotterdam, The Netherlands.

ALEXANDER K O L I N

Department of Biophysics UCLA School of Medicine Los Angeles, California 90024 G L E N N A . LANGER

Departments of Medicine and Physiology UCLA School of Medicine Los Angeles, California 90024 C . WALTON LILLEHEI

Department of Surgery University of Minnesota Medical School Minneapolis, Minnesota LEONARD M . L I N D E

Division of Pediatric Cardiology UCLA School of Medicine Los Angeles, California 90024 JERE H . MITCHELL

The Pauline and Adolph Weinberger Laboratory for Cardiovascular Research Department of Internal Medicine University of Texas Southwestern Medical School Dallas, Texas 75235 WILFRIED F . H . M . MOMMAERTS

Department of Physiology and the Los Angeles County Heart Association Cardiovascular Research Laboratory UCLA School of Medicine Los Angeles, California 90024 A R T H U R J. Moss Division of Pediatric Cardiology UCLA School of Medicine Los Angeles, California 90024 JOHN F . M U R R A Y

Department of Medicine and Cardiovascular Research Institute University of California San Francisco Medical Center San Francisco, California 94122 PETER

OSYPKA

Department of Bio-Engineering and Universitäts-Kinderklinik University of Kiel 23 Kiel, West Germany

ABRAHAM M . RUDOLPH

Cardiovascular Research Institute and Department of Pediatrics University of California San Francisco Medical Center San Francisco, California 94122 HERBERT D . RUTTENBERG*

Division of Pediatric Cardiology UCLA School of Medicine Los Angeles, California 90024 RONALD H . SELVESTER

ECG and Biomathematics Research Group and Cardiology Department Rancho Los Amigos Hospital Downey, California 90242 and University of Southern California School of Medicine Los Angeles, California NORMAN J . SISSMAN

Division of Pediatric Cardiology Stanford University School of Medicine Palo Alto, California EDMUND H . SONNENBLICK

Cardiology Branch, National Heart Institute Bethesda, Maryland 20014 and Cardiovascular Unit, Peter Bent Brigham Hospital Boston, Massachusetts 02115 MADISON S . SPACH

Division of Pediatric Cardiology Duke University School of Medicine Durham, North Carolina 27706 NORMAN S . T A L N E R

Department of Pediatrics Yale University School of Medicine and Yale-New Haven Hospital New Haven, Connecticut 06510 R O B E R T L . V A N CITTERS

Departments of Physiology and Biophysics University of Washington School of Medicine Seattle, Washington 98105 4 Present affiliation: Department of Pediatric Cardiology, University of Utah College of Medicine, Salt Lake City, Utah 8 4 1 1 2 .

LODEWYK H . S. VAN MIEROP

Department of Pediatrics and Human Development Center University of Florida College of Medicine Gainesville, Florida 32601 HOMER R . WARNER

Department of Biophysics and Bioengineering University of Utah College of Medicine Salt Lake City, Utah 84112 EARL H . WOOD

Section of Physiology Mayo Clinic and Mayo Foundation Rochester, Minnesota 55901

FOREWORD

Congenital heart disease in its various forms probably occurs in one per cent of all live births in the United States. Since four million infants are born annually, this means 40,000 cases of congenital heart disease each year—a considerable problem indeed. Though we still know surprisingly little about the natural history of the different congenital heart lesions, great progress has been made over the past two or three decades. Presently, diagnostic techniques permit assessment of even the most complicated anomalies, and corrective or palliative surgery is available for almost all cardiac malformations—but the necessity for and the effect of such surgical intervention are neither completely understood nor fully documented. Many gaps still exist in our knowledge of congenital heart disease. Work on etiology and teratogenesis of cardiac malformations has been minimal and only partially rewarding. The pathophysiology in congenital heart disease has also been only superficially studied. Pediatric cardiologists are hampered by a lack of knowledge of the normal cardiovascular physiologic events that take place with growth and development from the fetus to the adult. Such knowledge is essential if the problems mentioned are to be solved. Present changes in the direction of investigative cardiology indicate a shift in emphasis from description and repair of the individual lesions to an understanding of the more basic problems. New and more sophisticated techniques and instruments are available for such studies, but few cardiologists have the background to utilize the advances for the solution of basic problems. It seemed timely, therefore, to convene the leading investigators in the fields of cardiovascular embryology, physiology, and instrumentation to assess the present state of our knowledge and to delineate some future directions for research activity. F.H.A.

CONTENTS

S O M E NOTES ON THE HISTORY OF CONGENITAL H E A R T DISEASE

1

Forrest H. Adams DEVELOPMENT OF THE CARDIOVASCULAR SYSTEM T H E C E L L U L A R BASIS OF MORPHOGENESIS IN THE E M R R Y O N I C H E A R T ROBERT L.

7

DEHAAN

S O M E B I O C H E M I C A L AND A N A T O M I C E F F E C T S OF SODIUM S A L I C Y L A T E ON THE CHICK E M B R Y O HEART IRA H.

17

GESSNER

BLOOD PRESSURE IN C H I C K E M B R Y O S LODEWYK

H.

S. VAN

27

MIEROP

P A N E L DISCUSSION

37

COMMENTARY: WILLIAM

F.

FRIEDMAN

CARDIOVASCULAR PHYSIOLOGY IN THE NORMAL FETUS AND NEONATE CONTROL OF SYSTEMIC, P U L M O N A R Y , AND REGIONAL B L O O D F L O W IN THE F E T A L AND N E O N A T A L PERIODS NICHOLAS

S.

47

ASSALI

M E T A B O L I C AND R E F L E X INFLUENCES ON CARDIAC F U N C T I O N IN THE N E W B O R N S . EVANS

59

DOWNING

P A N E L DISCUSSION

101

CARDIOVASCULAR PHYSIOLOGY IN THE AHNORMAL NEWBORN T H E F E T A L CIRCULATION AND ITS ADJUSTMENTS AFTER B I R T H IN CONGENITAL H E A R T DISEASE

Abraham

M.

105

Rudolph

PATHOPHYSIOLOGY OF CARDIAC F A I L U R E IN THE N E W B O R N

119

Norman S. Talner PANEL

131

DISCUSSION

MYOCARDIAL FUNCTION AND ITS CELLULAR BASIS T H E V A R I A B L E CONTRACTILE STRENGTH OF THE H E A R T

Wilfried

F. H. M.

Mommaerts xiii

135

MECHANICAL ANALYSIS OF CARDIAC CONTRACTILITY

139

T H E MECHANICS OF CONTRACTION OF THE INTACT H E A R T

149

Allan J. Brady

JOHN ROSS, JR., AND EDMUND H. SONNENBLICK DETERMINANTS OF VENTRICULAR FUNCTION

J ERE H.

163

MITCHELL AND CHARLES B. MULLINS

P A N E L DISCUSSION

181

VENTRICULAR F U N C T I O N :

CLINICAL

ASPECTS

PRORLEMS IN THE M E A S U R E M E N T OF VENTRICULAR V O L U M E S

H. J. C.

185

SWAN 201

ASSESSMENT OF MYOCARDIAL FUNCTION IN CONGENITAL H E A R T D I S E A S E

PAUL G. AN

ANALYSIS

HUGENHOLTZ AND HENRY R.

OF

THE

DETERMINANTS

OF

WAGNER

VENTRICULAR

DIMENSIONS

AND

F O R C E - V E L O C I T Y RELATIONS IN M A N

231

EUGENE BRAUNWALD VENTRICULAR INTRACARDIAC SHUNTING MECHANISMS IN CONGENITAL H E A R T DISEASE

247

AARON R. LEVIN,

M. M. JARMAKANI, MADISON S. SPACH, RAMON V .

CANENT, JR., M. PAUL CAPP, JOHN P. BOINEAU, AND ROGER C. BARR PANEL DISCUSSION EXERCISE

265

PHYSIOLOGY

T E L E M E T R Y STUDY OF REGIONAL RLOOD F L O W IN EXERCISING SLED DOGS

Robert L. Van Citters and Dean L. Franklin

273

ALTERATIONS IN THE ACTIVITY OF THE ADRENERGIC NERVOUS S Y S T E M IN H E A R T FAILURE

289

EUGENE BRAUNWALD FUNCTIONAL EVALUATION OF CHILDREN WITH CONGENITAL H E A R T D I S E A S E RY RESPONSE TO M A X I M A L E X E R C I S E

295

STANLEY J. GOLDBERG P A N E L DISCUSSION S P E C I A L PHYSIOLOGIC

305 PROBLEMS

A N E M I A AND CARDIAC FUNCTION

309

JOHN F. MURRAY REGULATION OF T H E PULMONARY CIRCULATION

LEONARD M. LINDE AND DANIEL H.

321

SIMMONS

CARDIAC FUNCTION IN E X P E R I M E N T A L C O M P L E T E H E A R T BLOCK

331

HERBERT D. RUTTENBERG, ROBERT L. VAN CITTERS AND ROGER A. HURWITZ PANEL DISCUSSION

345

xiv

BIO-ENGINEERING ADVANCES I N CARDIOVASCULAR PHYSIOLOGY EXPLORATORY ELECTROCARDIOGRAPHY: USE OF ISOPOTENTLAL SURFACE M A P S

347

Sarah D. Blumenschein, Madison S. Spach, John T. Flaherty, John P. Boineau, Roger C. Ban and Thomas M. Gallie D I G I T A L COMPUTER MODEL OF A T O T A L BODY E C G

SURFACE M A P :

ADULT

M A L E TORSO SIMULATION W I T H LUNGS RONALD H.

369

SELVESTER, JOSEPH C. SOLOMON AND THOMAS

L.

GILLESPIE

RADIO TELEMETRY TECHNIQUES FOR MEASUREMENT OF BLOOD PRESSURE AND F L O W IN UNRESTRAINED A N I M A L S DEAN

L.

FRANKLIN, W.

NOLAN W.

377

SCOTT KEMPER,

ROBERT L.

VAN

CITTERS, AND

WATSON

EVOLUTION OF ELECTROMAGNETIC BLOOD FLOWMETERS ALEXANDER

383

KOLIN

P A N E L DISCUSSION

407

A SYSTEM FOR O N - L I N E COMPUTER ANALYSIS OF D A T A DURING H E A R T C A T H ETERIZATION

409

Homer R. Warner, R. M. Gardner, T. Allan Pryor, W. Clinton Day and William M. Stauffer USE OF VIDEOMETRY AND ELECTRONIC DATA-PROCESSING FOR H E M O D Y N A M I C INVESTIGATIONS BY ANGIOGRAPHIC TECHNIQUES EARL H.

WOOD

AND RALPH

E.

419

STURM

N A M E INDEX

435

SUBJECT INDEX

439

xv

SOME NOTES ON THE HISTORY OF CONGENITAL HEART DISEASE

F O R R E S T H. ADAMS Division of Pediatric Cardiology University of California Los Angeles, California

The history of man's knowledge of the embryology of the heart and of the existence of congenital heart disease can be traced back to Aristotle in the fourth century B.C. Subsequently, Fabricius, von Haller, Morgagni, Hunter, Spallanzani, Baillie, Rokitansky, Roger, Fallot, Eisenmenger, and Mall made significant observations. The first comprehensive volume on the subject, "On Malformations of the Human Heart", written by Thomas B. Peacock, was published in London in 1858 (23). It remained, however, for Maude Abbott (1868-1940) to bridge the gap between the early, purely descriptive knowledge of congenital heart disease and the modern Twentieth-Century era of precise diagnosis and eventual surgical treatment of these defects. Dr. Abbott was undoubtedly the most prolific contributor to our knowledge of congenital abnormalities of the heart and great vessels prior to 1940. Her first major report (1) appeared in 1908 in Osier & McCrae's System of Modern Medicine, and was based on an analysis of 412 cases of her own and the world's literature. In 1936, she published her Atlas of Congenital Cardiac Disease (2), which not only presented an analysis of 1000 cases seen by her, but also brought together the development and comparative anatomy of the reptilian, amphibian, and mammalian hearts. Now, at a time when it is extremely difficult to obtain information on the natural history of the various forms of congenital heart disease, her statistical table of congenital heart disease is particularly useful. Soon after Dr. Abbott's monograph appeared, J. W. Brown (7) published in England the first modern clinical text on congenital heart disease; it was somewhat premature, though, and thus was not widely read. In the period 1920-1940, clinicians began, as the result of Maude Abbott's careful work, to diagnose specific congenital heart lesions. Many ignored, however, "the study of the cardiac malformations because they were hopeless finalities in which the function of the physician was limited to matters of general advice and prognosis."* Suddenly, as the result of the pioneering " Edwards A. Park, in Foreword to Dr. Taussig's monograph on Congenital Malformations of the Heart (27). 1

2

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HEART

DISEASE

work of Gross & Hubbard in 1939 (14), it became possible to correct surgically a congenital heart lesion, patent ductus arteriosus. From this time on, it became essential for clinicians to diagnose correctly all noncyanotic heart lesions. Further impetus was given to clinicians by Gross & Hufnagel (15) and by Crafoord & Nylin (10), who demonstrated in 1945 that coarctation of the aorta could be treated successfully by surgical resection. In 1945, Blalock & Taussig (5) showed that a surgical palliative procedure, which increased pulmonary blood flow but did not correct the intracardiac lesion, greatly improved patients with tetralogy of Fallot. Clinicians then were forced to differentiate the various cyanotic heart lesions. During approximately the same period, three future Nobel laureates (Forssmann, Cournand, and Richards) were working on a technique, cardiac catheterization, which eventually revolutionized the diagnosis and evaluation of cardiac function and disease. Forssmann (12) was, in 1929, the first to show that the heart could be approached in vivo by the insertion of a tube into the vein of an arm. Later, Cournand (9) and Richards (24) used Forssmann's technique, primarily in the study of patients with shock. It was not long before the same technique was applied to the diagnosis of congenital heart disease (3, 4,8,11). Clinical pediatric cardiology, although dormant for many years, really had its beginnings in the decade of 1940. The rapid development of surgical procedures for correction or palliation of some congenital heart lesions, plus the availability of more precise diagnostic techniques such as cardiac catheterization, indicator dilution curves (16), and angiocardiography (25), stimulated many individuals to become interested in the field. The real leader at this time was Helen B. Taussig, then Associate Professor of Pediatrics at Johns Hopkins University (Figure 1). As a result of her earlier publications, plus her outstanding 1947 monograph Congenital Malformations of the Heart (27), she attracted physicians to come and study with her from all over the United States and many countries throughout the world. Dr. Taussig developed an uncanny ability to arrive at the correct clinical diagnosis as the result of meticulously gathering all the facts pertaining to the patient and carefully fitting them together in their proper relationships by a process of clear, logical thinking. Soon many physicians could see the possibilities for correcting virtually all of the congenital cardiac malformations as well as many of the acquired cardiac abnormalities. To do this, however, it would be necessary to open the heart itself. Initial attempts in this direction were applied to patients with pulmonary valvular stenosis (6) and with atrial septal defect (19, 26). In some instances (19, 26), hypothermia of the patient was used. The first official announcement of the satisfactory employment of a pump oxygenator for cardiopulmonary bypass was made in 1954 by Gibbon (13), who had been working on it for many years. Lillehei and associates (21), however, were the first successfully to close ventricular septal defects in pa-

HISTORY

OF

CONGENITAL

HEART

DISEASE

3

Figure 1. Helen B. Taussig. Taken in 1966, during her tenure as President of the American Heart Association.

tients, using the open heart technique; the first operations were accomplished using cross circulation. Almost immediately, the open heart technique was used by Lillehei and coworkers (20) for total correction of cyanotic lesions such as tetralogy of Fallot, pentalogy of Fallot, and pulmonary atresia. Interest in the diagnosis and treatment of congenital heart disease became widespread. Three new textbooks (17, 18, 22) appeared promptly on the subject, and research and training programs were initiated throughout America and Europe. In the decade of 1960, diagnostic techniques permit assessment of even the most complicated anomalies, while corrective or palliative surgery is available for virtually all cardiac malformations. Present

4

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changes in the direction of investigative cardiology indicate a shift in emphasis from description and repair to an understanding of the more basic problems. REFERENCES 1. ABBOTT, M. E., Congenital cardiac disease. In: Osier's Modern Medicine, Vol.

2. 3.

4.

5.

6. 7.

8. 9.

10.

IV (W. Osier and T. McCrae, Eds.). Lea & Febiger, Philadelphia, 1908: 323-425. , Atlas of Congenital Cardiac Disease. American Heart Association, New York, 1936. BALDWIN, E . DEF., MOORE, L . V., and NOBLE, R. P., The demonstration of ventricular septal defect by means of right heart catheterization. Am. Heart J., 1946,32: 152-162. BING, R. J., VANDAM, L . D., and GRAY, F. D., JR., Physiological studies in congenital heart disease. I. Procedures. Bull. Hopkins Hosp., 1947, 80: 107-120. BLALOCK, A., and TAUSSIG, H. B., The surgical treatment of malformations of the heart in which there is pulmonary stenosis or pulmonary atresia. }. Am. Med. Ass., 1945,128: 189-202. BROCK, R. C., Pulmonary valvulotomy for the relief of congenital pulmonary stenosis: report of three cases. Brit. Med. J., 1948, 1: 1121-1126. BROWN, J. W., Congenital Heart Disease. Staples, London, 1939. COURNAND, A., BALDWIN, J. S., and HIMMELSTEIN, A., Cardiac Catheterization in Congenital Heart Disease; A Clinical and Physiological Study in Infants and Children. Commonwealth Fund, New York, 1949. COURNAND, A., and RANGES, H. A., Catheterization of the right auricle in man. Proc. Soc. Exp. Biol. Med., 1941,46: 462-466. CRAFOORD, C., and NYLIN, G., Congenital coarctation of the aorta and its surgical treatment. J. Thorac. Cardiov. Surg., 1945,14: 347-361.

1 1 . DEXTER, L . , HAYNES, F . W . , BURWELL, C . S., EPPINGER, E . C . , SOSMAN, M . C . ,

12. 13.

14.

15. 16.

and EVANS, J. M., Studies of congenital heart disease. III. Venous catheterization as a diagnostic aid in patent ductus arteriosus, tetralogy of Fallot, ventricular septal defect and auricular septal defect. J. Clin. Invest., 1947,26: 561-576. FORSSMANN, W., Die Sondierung des rechten Herzens. Klin. Wschr., 1929, 8: 2085-2087. GIBBON, J. H., JR., Discussion of: Warden, H. E., Cohen, M., Read, R. C., and Lillehei, C. W., Controlled cross circulation for open intracardiac surgery; physiologic studies and results of creation and closure of ventricular septal defects. J. Thorac. Cardiov. Surg., 1954,28: 343. GROSS, R. E., and HUBBARD, J. P., Surgical ligation of a patent ductus arteriosus: report of first successful case. J. Am. Med. Ass., 1939, 112: 729-731. GROSS, R. E., and HUFNAGEL, C. A., Coarctation of aorta: experimental studies regarding its surgical correction. New Eng. J. Med., 1945, 233 : 287-293. HAMILTON, W . F., and REMINGTON, J. W., Comparison of the time concentration curves in arterial blood of diffusible and non-diffusible substances

HISTORY

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HEART

DISEASE

5

when injected at a constant rate and when injected instantaneously. Am. J. Physiol, 1948,148: 35-39. 17. KEITH, J. D., ROWE, R. D., and VLAD, P., Heart Disease in Infancy and Childhood. Macmillan, New York, 1958. 18. KJELLBERG, S. R., MANNHEIMER, E., RUDHE, U., and JONSSON, D., Diagnosis of Congenital Heart Disease. Year Book Publishers, Chicago, 1955. 19. LEWIS, F. J., and TAUFIC, M., Closure of atrial septal defects with the aid of hypothermia; experimental accomplishments and the report of one successful case. Surgery, 1953, 33: 52-59. 2 0 . LILLEHEI, C . W . , COHEN, M . , WARDEN, H . E . , READ, R . C . , AUST, J . B . , D E -

WALL, R . A., and VARCO, R. L., D i r e c t vision intracardiac surgical cor-

rection of the tetralogy of Fallot, pentalogy of Fallot, and pulmonary atresia defects: report of first ten cases. Ann. Surg., 1955, 142: 418-445. 2 1 . LILLEHEI, C . W . , COHEN, M . , WARDEN, H . E . , ZIEGLER, N . R . , a n d VARCO, R . L . ,

The results of direct vision closure of ventricular septal defects in eight patients by means of controlled cross circulation. Surg. Gynec. Obstet.,

22.

1 9 5 5 , 1 0 1 : 446-466.

A. S., Pediatric Cardiology. Saunders, Philadelphia, 1957. of the Human Heart toith Original Cases and Illustrations. London, 1858. RICHARDS, D. W., JR., The circulation in traumatic shock in man. Harvey Led., 1943-44, 39 : 217-253. ROBB, G. P., and STEINBERG, I., A practical method of visualization of the chambers of the heart, the pulmonary circulation, and the great blood vessels in man. J. Clin. Invest., 1938,17: 507. SWAN, H., ZEAVIN, I., BLOUNT, S. G., JR., and VIRTUE, R. W . , Surgery by direct vision in the open heart during hypothermia. J. Am. Med. Ass., 1953, 153: 1081-1085. TAUSSIG, H. B., Congenital Malformations of the Heart. Commonwealth Fund, New York, 1947. NADAS,

23. PEACOCK, T. B., On Malformations

24. 25.

26.

27.

THE CELLULAR BASIS OF MORPHOGENESIS IN THE EMBRYONIC HEART R O B E R T L . DEHAAN Department of Embryology Carnegie Institution of Washington Baltimore, Maryland

It is my purpose in these remarks to reemphasize that, when we watch an organ develop in an embryo, what we see is the activities of cells ( 1 3 , 1 4 , 1 6 ) . Any organ at a given stage of development is merely the manifestation of the structural and behavioral spectrum of the cells of which it is comprised —cells which act as individuals, and in concert with other cells in groups. During development of the heart—or of any other organ—its component cells participate in three fundamental processes, simultaneously and interdependently. These are growth, or cellular multiplication; differentiation, the appearance of new characteristics in cells; and morphogenesis, the capacity of cells to move, to adhere, and to mold themselves into functional organs and tissues ( 1 1 , 1 4 ) . Each of these processes in the embryo is normally held under careful control and all three are maintained in delicate balance. If a localized burst of mitotic activity occurs a little too soon or a little too late, if a group of cells develops differential adhesiveness to other cells of type A instead of type B, if a sheet of cells bulges in instead of out, the whole system may be disrupted and an abnormal organ, or congenital defect, will result. Whether any given cell divides at any given moment in a tissue is, however, clearly dependent upon information coded into the genome of that particular cell and upon influences exerted on that cell from its environment. Similarly, whether a cell develops an adhesiveness for a newly apposed surface will also depend upon conditions in that cell's local environment at the moment contact is made and upon gene-directed synthesis of adhesive moieties in the cell's membrane. If we are to ask questions about the etiology and pathogenesis of congenital heart defects we would be well advised to think in terms of the properties and behavior of the cells which form the tissue in question. If we want to know why ventricular septal defects arise, we must first examine the behavioral spectrum and regulatory mechanisms which characterize the cells 7

8

CONGENITAL

HEART

DISEASE

that normally form the septum. We are now in a position to do so. We now have a sufficient armamentarium of techniques—techniques of experimental embryology and microsurgery (29), of cytology and cytogenetics (4), of biochemistry and histochemistry—to begin analyzing the properties of the cells which normally form any region or part of an organ. And, perhaps even more important, the techniques of cell and organ culture make it possible for us to isolate cells or tissues as model systems in order to examine, one by one, the variables and mechanisms underlying morphogenetic events. Let us turn, then, to two examples of developmental processes in the heart which are more or less related to congenital heart disease to see if we can ask meaningful questions about them using the experimental techniques available to us. DEXTROCARDIA AND D I F F E R E N T I A L

GROWTH

In the clinical entity dextrocardia, the heart assumes a position on the right side of the thorax with its apex pointing to the right, rather than on the left side, pointing left. This condition is of special interest to the embryologist because, developmentally, dextrocardia appears to represent a reversal in the direction of the primitive cardiac loop (34). According to the description in most textbooks of embryology, the heart loops into an S-shaped configuration because of external mechanical forces. The primitive tubular heart, it is said, grows faster than the epicardial space in which it forms. Therefore, it must bend. A simple exercise in microdissection, however, places this explanation in doubt. If the S-looped heart is dissected from a living 48-hour chick embryo (stage 12) by cutting through the arterial arches and venous roots, the heart shows no tendency to spring back into a straight tube, as would be expected if it were held by external constraints. In fact, it retains its curved configuration, which indicates that this shape is intrinsic to the heart itself. Moreover, it is possible to place the rudimentary heart in organ culture, isolated from the body and pericardial cavity, at a stage when it is in the straight tubular form. Bacon (1) was the first to perform this experiment with amphibian hearts. More recently, Butler (3) has succeeded with the chick heart. Both investigators found that the straight cardiac tube formed itself into a C- or S-configuration similar to unoperated controls. Clearly, then, dextral looping does not result from external mechanical constraints. Rather, these results are suggestive of intrinsic bending or torsional forces generated within the tubular heart itself. Three possibilities come to mind when one attempts to explain how such intrinsic forces might be produced: (a) localized differential growth rates, (b) initial localized areas of high or low cell density, and (c) initial asymmetry in rate of development (28). If the left and right halves of the heart enlarged at different rates during the hours subsequent to the formation of the straight primitive tube, like a bimetallic thermoelectric device, the straight tube would bend to one side.

MORPHOGENESIS

IN T H E

EMBRYONIC

HEART

9

Furthermore, if the two halves were characterized by small localized regions of high and low mitotic activity, complex and tortuous curves of the tube could result. Such localized differential regulation of mitotic activity in different parts of the heart has been reported at later embryonic stages, during septation and final molding of the fetal organ (18); there is also evidence suggestive of such local control during early heart formation (28). Even with constant and equal distribution of mitotic activity throughout the heart, localized areas of high cell density would tend to grow faster than areas of similar initial volume which contained fewer cells. Asymmetric distribution of areas of different density could also produce curvature and asymmetric enlargement of the cardiac tube. Finally, if the two precardiac rudiments were to develop at different rates in a cephalocaudal direction—that is, if more of one rudiment differentiated and became incorporated into the heart tube per unit time than the other— this development also could result in asymmetric stresses and curvature despite uniform distribution of mitotic activity (28, 29). It should be noted, as emphasized recently by Orts Llorca & Gil (23), that even at the earliest stage the "straight tubular heart" is not a perfectly uniform symmetrical cylinder. In the chick, as early as stage 9 (seven somites), when the fused tubular heart has just been established, there is already a slight bulge on the right side of the conoventricle and a tilt to the entry of the omphalomesenteric veins (29). Even the asymmetry of the bulboventricular and atrioventricular sulci is indicated. Moreover, the same primary asymmetry has been described in human hearts at equivalent early stages ( 7 ) . One method for testing the three hypotheses outlined above has been provided by the technique of autoradiography (20). Before a cell can divide it must duplicate its chromosomal complement; that is, it must synthesize a large quantity of DNA. It normally does this some hours before the cell actually divides. If, during this period of active synthesis of DNA, the cell is confronted with a nucleic acid precursor labeled with a radioactive isotope such as tritium, the labeled molecules are incorporated into the chromosomal strands. Such labeled nuclei can be identified subsequently by placing the cells in contact with a photosensitive emulsion, which produces clusters of silver grains wherever products of radioactive emission penetrate it. With this technique the number of cells preparing for division in any part of an embryo can be readily determined. This number has been taken as an index of the localized growth rate. Sissman (27) has reported an application of this technique to a study of differential growth rates in the embryonic heart. He incubated chick embryos at stages 10 to 17 (approximately 35 hours to three days of incubation) in the presence of tritium-labeled thymidine for one hour before fixing the embryos in formalin. He then sectioned the embryos histologically and coated the sections with photographic emulsion. After a period of exposure and treatment of the slides with photographic developer, Sissman was able to

10

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count the labeled cells in each cross section of the heart, and thereby determine how many cells were preparing for mitosis. In the embryo illustrated in his paper (an embryo of 15 somites), for example, three to four times more cells were mitotically active along the greater (convex) curvature of the ventricular loop than in the region of the lesser curvature. In 1906, Mollier (22) termed the crescentic layer of thickened splanchnic mesoderm in the early-somite embryo the "cardiogenic plate". Since the heart tube develops from the bilaterally paired wings of this cardiogenic crescent, the next question naturally arises: Do these two lateral regions contribute equally to the straight tubular heart? My colleague, Dr. Helge Stalsberg, has recently worked out an elegant technique for answering this question (28). He soaked tiny pieces of thin cellulose membrane in H3-thymidine and applied them to the endodermal surface of embryos at the cardiogenic crescent stage while they were maintained in vitro. Each piece covered either the right or left lateral half of an embryo; thus, only the right or left wing of the cardiogenic crescent took up the label. After 20 minutes the label-soaked membranes were removed, and the embryos were washed and reincubated for 24 hours. When these embryos had formed tubular hearts they were fixed, sectioned, and prepared for autoradiography. Examination and graphic reconstruction of these hearts at the straight tube stage (stage 10) indicated that the ventral line of juncture of labeled and unlabeled epimyocardium coincided almost exactly with the geometric ventral midline of the tube. At later stages, however, after curvature of the primitive heart, the line of juncture of the two wings of the crescent no longer followed the ventral midline. Instead, it coursed along the greater curvature of the bulging ventricle; that is, it had moved far to the embryo's right side. This shift in position of the ventral midline in the chick heart is similar to that reported for the human heart from histological study of embryos in the Carnegie collection (32). Thus, not only does the cardiac tube curve to the right, it also undergoes a remarkable torsion in that direction as well. Counts of cells in the labeled and unlabeled portions in such preparations indicate that in the cephalic portion of the stage 12 chick heart (bulbus and prospective right ventricle) significantly more cells were contributed to the myocardium from the right side than from the left. In the caudal part of the tubular heart, which is prospective left ventricle, this relation was reversed, more cells originating from the left limb of the cardiogenic crescent than from the right (28). There is another way to obtain an indication of the growth potential of the various portions of each half of the tubular heart. Some time ago I worked out a microsurgical method for preventing fusion of the two lateral cardiac primordia in the early chick, thus producing cardia bifida embryos (8). When a cut is made in the middle of the endodermal fold that forms the anterior intestinal portal, each lateral wing of the cardiogenic crescent

MORPHOGENESIS

IN THE

EMBRYONIC

HEART

11

produces a tubular half-heart, including a conal region, a prospective right ventricle, and a prospective left ventricle. When such cardia bifida embryos were examined at stages 10 to 11 (10 to 13 somites), before dextral looping in the intact heart had progressed very far, the two half-hearts were approximately equal in size. However, at stages 12 to 13 (15 to 19 somites), the anatomic left ventricle which had formed from the left limb of the cardiogenic crescent was larger than that formed from the right limb, while the right ventricle from the right side was larger than its mate. These results suggest that during the 12 to 15 hours intervening between stage 10 and stage 13, the left ventricular tissue contributed by the left wing of the cardiogenic crescent grew at a more rapid rate than the equivalent tissue from the right wing of the crescent, while the situation was reversed in the tissue forming the more cephalad anatomic right ventricle. If the two half-hearts were instead fused to form a single tube, the predicted result of these differential growth regions would be to swing the ventral midline and entire tubular heart to the embryo's right (33). If we knew precisely which portions of the tubular heart were formed from each region of the left or right mass of cardiogenic mesoderm, we could ask the next question: Are the specific rates of mitosis or enlargement of small localized regions of the tubular heart already determined in the precardiac mesoderm cells destined to form that area? To answer this question, a method is needed for mapping the precardiac mesoderm in the early embryo before the heart rudiments differentiate. Several such mapping methods exist and have been applied to precardiac tissue. Rawles (25) explanted fragments of the blastoderm to the chorioallantoic membrane of host embryos according to systematic patterns in order to determine which fragments carried heart-forming capacity. We have traced the movements of splanchnic mesoderm into the forming heart in situ, using techniques of time-lapse cinematography (9, 10) and autoradiography (26, 29). From these studies it has become apparent that each portion of the cardiogenic crescent contributes to a specific region of the tubular heart. The cardiogenic mesoderm which lies in the cephalic and midportion of the crescent forms the conoventricular parts of the heart, while the right and left ventricles develop from more posterior mesoderm in the two wings of the crescent. Cells at the caudolateral edge of each wing of the heartforming material differentiate into atrial and sinoatrial structures. Thus, we are in a position to examine the mitotic rates or growth potentials of cells in the cardiogenic mesoderm known to contribute to specific regions of the tubular heart. If no evidence of localized differential growth is found, we can look for initial asymmetries, as mentioned earlier, as the probable mechanism of curvature. If differences in regional mitosis are noted, one intriguing possibility will be to search for specific mitotic regulators of the type reported recently for other tissues (2, 24, 31).

12

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CELL AGGREGATION AND CARDIOGENESIS

Prior to differentiation of the tubular heart, between stages 6 and 8, there is a surge of movement of the precardiac mesoderm in the cardiogenic crescent, cephalad relative to the underlying endoderm. This movement has been seen on time-lapse films of intact embryos in culture (9) and has been confirmed with autoradiographic mapping methods (26). It was thought originally that it represented the autonomous locomotor activities of clusters of mesoderm cells, migrating anteromesially on the endodermal substratum (12). More recent evidence, however, suggests that such movements of cells through tissues may be relatively rare (35) and that, instead, each lateral region of splanchnic mesoderm moves as a sheet (29), foreshortening towards a point near the cephalic border of each wing of the cardiogenic crescent. Moreover, as this movement proceeds, a wave of differentiation of mesoderm into functional cardiac tissue is initiated, first in the anteriormost portions of the crescent and proceeding posteriorly. If this description represents accurately the events in vivo, it would not be difficult to find an underlying mechanism to explain it. As cells embark on new differentiative paths, their adhesive properties are known to be among the first to change (5, 12, 19). In an intriguing article entitled, "What We Do not Know about Differentiation", Grobstein (17) pointed out that in most tissues the first recognizable differentiative changes are preceded by a specific morphogenetic event, namely condensation or aggregation of the cells into tightly knit collectives. That this phenomenon applies to differentiation of the heart is obvious upon observation of embryonic precardiac mesoderm differentiating in culture, or even from histological examination of early forming hearts. A region of condensation occurs first in the anteriormost part of each wing of the cardiogenic crescent and gradually spreads caudalwards, presaging in each area the differentiation of beating heart cells. Since the endoderm and mesoderm are firmly anchored together in the area surrounding the cephalic tip of the stiff rod of notochord, the condensation would tend to draw the mesenchymal posterior splanchnic mesoderm cephalad, producing the observed movement. I referred earlier to the desirability of finding model systems for studying the behavioral properties of cells under conditions where one or a small number of variables can be manipulated at a time. Recently a fortunate observation revealed a system which appears to be an excellent model for studying such aggregative behavior in cardiac tissue. Over the past few years, we have been refining techniques for dissociating embryonic hearts into their component cells and culturing them at low densities, so that each cell is isolated from contact with neighbors after the cells attach to the culture dish (15). After a period of incubation in growth medium, however, cells gradually come into contact with more and more neighbors, as the cell density on the plate increases. For a study of the phys-

MORPHOGENESIS

IN

THE

EMBRYONIC

HEART

13

iological effects of potassium ions in switching off spontaneous rhythmic activity of these cells in actively growing cultures (15), seven-day heart cells were grown in media identical with one another except in their content of this ion. Cells were plated in media containing 1.26, 4.20, or 12.10 mEq/liter K+. After four days in culture, it was noted that the cells were clumped into an area of very high density at or near the center of the plates containing low-potassium medium, whereas in medium containing 12 mEq/liter K+, the cells were distributed evenly over the bottom of the dish. Cultures were set up with the same three media so that this phenomenon could be further investigated. At 24-hour intervals, the cell density (cells/mm 2 of dish surface) was counted at the center and in five concentric regions on each plate. In addition, the degree of intercellular contact was measured in each of these regions in terms of the percentage of the peripheral surface of each cell found to be in contact with neighboring cells (16). It was found that the total density of cells per plate was the same in all three media initially (i.e., 24 hours after inoculation of the plates) and terminally. After four days of active growth, the cell density per plate had increased approximately twelvefold in all three media. However, again, in low-potassium medium cells were densely aggregated in the center of each plate. In high-potassium medium they were homogeneously distributed on the plates. In all three media, the percentage of cell contact increased as the cell density increased. In low-potassium medium, however, it increased much more rapidly than with higher potassium levels. When small areas of equal cell density were compared, each cell in low-potassium medium had an average of 80 per cent of its circumference in contact with neighbors at a density of about 800 cells/mm2. At that same cell density in high-potassium medium, the cells had only 48 per cent of their peripheral surfaces in contact with neighbors. Thus it appears that heart cells increase their degree of intercellular contact, or condense into aggregates, in low-potassium medium. At high levels of potassium they tend to minimize intercellular contact. Further experiments demonstrated that this effect is not specific to potassium ions, but is apparently an osmolar influence, produced equally well by sodium or sucrose. The possible relevance of the behavior of these cultured heart cells to the processes of cardiogenesis in the early intact embryo is intriguing and speculative. But it must be noted that during the entire period of early heart formation, until at least stage 14 (about three days of incubation in the chick), the embryo rests in a milieu of yolk and albumin which contains potassium at a concentration approximately ten times that found later in the amniotic fluid or fetal serum (15). Cells in a region in which this extraordinary ionic level was reduced would tend to cluster together—that is, if the prediction from our cell "model" system is valid. Thus, we are left with the question: Do precardiac cells first develop the ability to manipulate their ionic

14

CONGENITAL

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DISEASE

microenvironment before undergoing the "primary" morphogenetic event of aggregation ( 5 , 1 7 ) ? It is also interesting that several investigators have recently reported specific regulators of cell aggregation or adhesiveness (6, 21, 30). Is it possible that the effects of any of these agents might be mediated via influences on the ionic environment of the cells? The answers to these questions await further experiments. REFERENCES 1. 2. 3.

4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18.

Self-differentiation and induction in the heart of Amblystoma. J. Exp. Zool., 1945,98: 87-125. BULLOUGH, W. S., LAUBENCE, E . B . , IVERSEN, O . H . , and ELGJO, K., The vertebrate epidermal chalone. Nature (London), 1967, 214 : 578-580. BUTLER, J. K., An Experimental Analysis of Cardiac Loop Formation in the Chick. M. A. Thesis, University of Texas, 1952. CAMPBELL, M., Causes of malformations of the heart. Brit. Med. J., 1965, 2: 895-904. CURTIS, A. S. G., Cell contact and adhesion. Biol. Rev., 1962, 37: 82-129. CURTIS, A. S. G., and GREAVES, M . F . , The inhibition of cell aggregation by a pure serum protein. J. Embryol. Exp. Morph., 1965, 13: 309-326. DAVIS, C. L., Development of the human heart from its first appearance to the stage found in embryos of twenty paired somites. Carnegie Inst. Washington Contrib. Embryol., 1927,19: 245-284. D E H A A N , R . L . , Cardia bifida and the development of pacemaker function in the early chick heart. Develop. Biol., 1959, 1: 586-602. , Migration patterns of the precardiac mesoderm in the early chick embryo. Exp. Cell Res., 1963,29: 544-560. , Organization of the cardiogenic plate in the early chick embryo. Acta Embryol. Morph. Exp., 1963,6: 26-38. , Oriented cell movements in embryogenesis. In: Biological Organization at the Cellular and Supercellular Level (R. J. C. Harris, Ed.). Academic Press, London, 1963: 147-165. , Cell interactions and oriented movements during development. J. Exp. Zool., 1964,157: 127-138. , Morphogenesis of the vertebrate heart. In: Organogenesis (R. L. DeHaan and H. Ursprung, Eds.). Holt, Rinehart & Winston, New York, 1965: 377-419. —Development of form in the embryonic heart; an experimental approach. Circulation, 1967,35: 821-833. , Regulation of spontaneous activity and growth of embryonic chick heart cells in tissue culture. Develop. Biol, 1967,16: 216-249. , Emergence of form and function in the embryonic heart. Develop. Biol., 1968, Supp. 2: 208-250. GROBSTEIN, C., What we do not know about differentiation. Am. Zool., 1966, 6: 89-95. GROHMANN, D . , Mitotische Wachstumintensität des embryonalen und fetalen

BACON, R . L . ,

MORPHOGENESIS

19.

20. 21.

22. 23. 24.

25. 26.

27. 28. 29.

30. 31.

IN T H E

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HEART

15

Huhnchenherzens und ihre Bedeutung für die Entstehung von Herzmissbildungen. Zsehr. Zellforsch., 1961, 55:104-122. JONES, K. W., and ELSDALE, T. R., The culture of small aggregates of amphibian embryonic cells in vitro. J. Embryol. Exp. Morph., 1963, 11: 135154. KOPRIWA, B. M., and LEBLOND, C. P., Improvements in the coating technique of radioautography. J. Histochem., Cytochem., 1962,10: 268-284. LILIEN, J. E., and MOSCONA, A. A., Cell aggregation: its enhancement by a supernatant from cultures of homologous cells. Science, 1967, 157: 70-72. MOLLIER, S., Die erste Anlage des Herzens bei den Wirbeltieren. In: Handbuch der vergleichenden und experimentellen Entwickelungslehre der Wirbeltiere, Vol. 1/1-2 (O. Hertwig, Ed.). Fischer, Jena, 1906: 1020-1051. ORTS LLORCA, F., and G I L , D. R., A causal analysis of the heart curvatures in the chicken embryo. Roux Arch. Entwmech., 1967, 158 : 52-63. PLOTKIN, S. A., and VAHERI, A., Human fibroblasts infected with Rubella virus produce a growth inhibitor. Science, 1967, 156: 659-661. RAWLES, M. E., The heart-forming areas of the early chick blastoderm. Physiol. Zool., 1943,16: 22-42. ROSENQUIST, G. C., and D E H A A N , R. L., Migration of precardiac cells in the chick embryo: a radioautographic study. Carnegie Inst. Washington Contrib. Embryol., 1966,38: 111-121. SISSMAN, N. J., Cell multiplication rates during development of the primitive cardiac tube in the chick embryo. Nature (London), 1966, 210: 504-507. STALSBERG, H., The origin of heart asymmetry: right and left contributions to the early chick embryo heart. Develop. Biol., 1969, 19: 109-127. STALSBERG, H., and D E H A A N , R. L . : The precardiac areas and formation of the tubular heart in the chick embryo. Develop. Biol, 1969, 19: 128-159. TAYLOR, A. C., Cell adhesiveness and the adaptation of cells to surfaces. In: Biological Interactions in Normal and Neoplastic Growth (M. B. Brennan and W. L. Simpson, Eds.). Little, Brown; Boston, 1962: 169-182. TOZER, B. T., and PIRT, S. J., Suspension culture of mammalian cells and macromolecular growth-promoting fractions of calf serum. Nature (London), 1964,201: 375-378.

3 2 . VAN MIEROP, L . H . S., ALLEY, R . D . ,

KAUSEL, H . W . , a n d STRANAHAN, A . ,

Pathogenesis of transposition complexes. I. Embryology of the ventricles and great arteries. Am. J. Cardiol., 1963, 12: 216-225. 33. VAN PRAAGH, R., and D E H A A N , R. L . : Morphogenesis of the heart: mechanism of curvature. Carnegie Inst. Washington Yearbook, 1967, 65: 536-537. 34. VAN PRAAGH, R., VAN PRAAGH, S., VLAD, P., and KEITH, J. D., Anatomic types of congenital dextrocardia; diagnostic and embryologic implications. Am. J. Cardiol., 1964,13: 510-531. 35. WESTON, J. A., and ABERCROMBIE, M., Cell mobility in fused homo- and heteronomic tissue fragments. J. Exp. Zool., 1967, 164 : 317-323.

SOME BIOCHEMICAL AND ANATOMIC EFFECTS OF SODIUM SALICYLATE ON THE CHICK EMBRYO HEART*

IRA H.

GESSNER

D e p a r t m e n t of Pediatrics University of Florida College of Medicine Gainesville,

Florida

"Cardiac jelly" is the term used by Davis (3) for the elastic semisolid material present between the endocardium and epimyocardium of the early tubular embryo heart. In previous reports, chick embryo cardiac jelly was shown to contain significant amounts of acid mucopolysaccharides ( 5 ) and an experimental model was devised to study radioactive sulfate incorporation into cardiac jelly as a measure of acid mucopolysaccharide synthesis ( 4 ) . This system is being used to investigate the hypothesis that disturbance in the acid mucopolysaccharide content of cardiac jelly is related to abnormal cardiac development. Salicylates have been shown to be teratogenic in the chick (9) and in mammals (11, 13, 14). Cleft palate, skeletal and vascular malformations have been produced in the mouse (11, 13) and there is much evidence to support the contention that the pathogenesis of these defects is related to the established fact that salicylates inhibit mucopolysaccharide synthesis. Salicylates have never previously been identified as causing congenital heart defects and no information exists on their effect on the embryo heart. The purpose of this report is to identify sodium salicylate as a cardiac teratogen in the chick and to document some of its effects on the acid mucopolysaccharide content of the chick embryo heart. Preliminary studies on the effect of sodium salicylate on the mouse embryo heart are also included. METHODS

White Leghorn chick eggs, used for all experiments, were incubated at 38.5°-39.5°C. Sodium salicylate injections were carried out during the first 48 hours of incubation. The sterile solution of sodium salicylate contained the total dose desired in 0.05 ml, injected through the air sac into the middle ° This work was carried out during the author's tenure of an Advanced Research Fellowship of the American Heart Association and was supported by the Heart Association of Palm Beach and Martin Counties (Florida) and by a Grant-in-Aid from the American Heart Association. 17

18

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DISEASE

of the yolk. Controls consisted of eggs injected with 0.05 ml of either water or saline, and uninjected eggs. The hole in the shell was closed with wax and the eggs returned to the incubator. Eggs were candled daily and the mortality recorded. Proof of death was obtained in all embryos by opening the eggs, although after 72 hours of incubation candling is virtually 100 per cent accurate. In morphologic experiments, embryos surviving to at least 17 days of incubation were autopsied specifically for the presence of cardiac and great vessel abnormalities. Younger embryos were not examined, as their size was too small for conventional autopsy techniques and facilities for serial sectioning of all embryos were not available. Thus, the results are biased by the necessity of an embryo surviving almost to completion of incubation in order to be included in the analysis. This bias would most likely be towards minimizing the incidence of abnormalities detected. Experiments using radioactive sulfate were carried out as follows. In some experiments eggs were injected with sodium salicylate as described above, then incubated until stage 18-19 of Hamburger & Hamilton (6). The eggs were opened, the hearts dissected free, washed with saline, and then incubated in modified Tyrode's solution (4) containing Na-/f'SO.i. In other experiments, normal embryos of stage 18-19 were gathered, their hearts removed and incubated in Tyrode's solution containing Na235S04 and various concentrations of sodium salicylate. A full description of the experimental technique, including the methods of recovery of the incorporated isotope, was given in a previous report (4). For both the in vivo and in vitro sodium salicylate experiments, controls consisted of similar groups of embryos exposed to identical doses of parahydroxybenzoic acid, a structural isomer of sodium salicylate. Indirect identification of the types of acid mucopolysaccharides was performed on 35S-sulfate labeled chick hearts by the cetylpyridinium chloride (CPC)-cellulose column technique of Antonopoulos and coworkers (1). The application of this method to the current experiment has been described previously (5). Mouse experiments utilized pregnant, primiparous animals of A/Jax strain. Mating was carried out at night and identification of a vaginal plug denoted day zero of pregnancy. The animals were sacrificed on the tenth day by a sharp blow to the head. The abdomen was opened immediately, the embryos removed, and their hearts dissected free. At this stage, the mouse embryo heart is a simple tubular structure. The hearts were washed in Tyrode's solution at 38°C. for 30 minutes and then incubated for two hours at 38 °C. in Tyrode's solution containing 35S-sulfate, and in similar solutions containing several concentrations of either sodium salicylate or parahydroxybenzoic acid. Under these conditions the hearts continued to beat regularly. The incubation was stopped with two per cent monoiodoacetic acid and the hearts washed once in a saturated solution of sodium sulfate and three times in saline. The tissue was dried overnight on aluminum foil

EFFECTS

OF S O D I U M

SALICYLATE

19

strips and the strips then weighed on a Cahn gram electrobalance (Model G) to the nearest microgram. The tissue was removed from the foil strip, placed in a test tube, and the foil reweighed. The dry weight of the tissue to the nearest microgram was thus obtained by the difference. The remainder of the embryo with heart removed was similarly dried and weighed, following an identical period of incubation in plain Tyrode's solution without isotope. Recovery of the isotope and the pattern of its distribution according to the CPC-cellulose column technique was carried out in the same manner as for chick tissue. In some animals a single intraperitoneal injection of 10 mg/20 g body weight of either sodium salicylate or parahydroxybenzoic acid was given on gestational day 9. The animals were sacrificed 24 hours later, the embryos recovered, and their hearts removed. Dry weights of the hearts and embryos were obtained as described. RESULTS

A direct relation between injected doses of sodium salicylate and mortality was established. Figure 2 illustrates this effect for sodium salicylate injected at 48 hours incubation age. Quite similar curves were obtained for injection at other times during the first 48 hours of incubation. Embryos surviving to at least 17 days of incubation revealed a definite cardiac teratogenic effect of sodium salicylate. Anomalies produced included isolated ventricular septal defect, ventricular septal defect with right ventricular outflow tract obstruction, pulmonary atresia with intact ventricular septum, and pulmonary atresia with ventricular septal defect. In some specimens, aortic arch anomalies, such as bilateral arch of the aorta, were present without any cardiac anomaly. The highest incidence of cardiac and/or great vessel abnormalities was 15 per cent (4/26) in embryos injected with 20 mg of sodium salicylate. The incidence was 11 per cent (4/36) in the embryos injected with 15 mg, and 4 per cent (2/45) in the 10 mg group. No anomalies were seen in the 5 mg group (0/42), and none was seen in control specimens. As has been reported previously ( 4 ) , sodium salicylate inhibits in vitro incorporation by isolated chick hearts in direct proportion to the drug concentration. The pattern of distribution of the incorporated isotope in salicvlate-treated tissue by the CPC-cellulose column technique is seen in Table 1. In Table 2, the average of the values shown in Table 1 is compared with average values from untreated chick heart tissue. It is apparent that, for treated hearts, more isotope appears in the 0.6M MgCl2 fraction and less in the 1.2M MgCL fraction. Thus, in addition to a suppression of total isotope incorporation, certain acid mucopolysaccharides are apparently suppressed more than others. When 20 or 30 mg of sodium salicylate are injected into the egg yolk on the first day of incubation (a dose which eventually is nearly uniformly le35S-sulfate

20

CONGENITAL HEART

DISEASE

Figure 2. Effect of injection of 5 dosages of sodium salicylate on subsequent survival of chick embryos. All injections were 0.05 ml given directly into the yolk via the air sac at 48 hr. incubation age.

thai), an interesting phenomenon results. If these hearts are removed on day 3, washed to remove the salicylate, and then incubated with isotope, the amount of isotope incorporated is significantly greater than that of control hearts (Figure 3); this effect is opposite to the inhibition of isotope incorporation seen in vitro. Column analysis of this tissue reveals no significant change from control values. TABLE 1 CHICK C O L U M N S IN VITRO SODIUM SALICYLATE

(Per Cent Recovery) Column Number Eluant

CPC NaCl 0.6M MgCU 1.2M MgCl 2 6 N HCl

6 6

9 5 69 16

10 4 67 17

7 5 61 25

6 6 64 23

68 19

1

1

1

1

1

E F F E C T S

O F

S O D I U M TABLE

EFFECT

OF SODIUM S A L I C Y L A T E

S A L I C Y L A T E

2

ON D I S T R I B U T I O N

OF IN V I T R O

T H R E E - D A Y CHICK EMBRYO

Elu ant

Control

CPC NaCl 0.6M MgCh 1.2 M MgCh 6N HCl

8 3 56 31 1

48

-

40

-

35S

INCORPORATION

HEARTS

Sodium Salicylate 8 4 67 19 1

32 -

X

E

24

16

-

UN INJECTED

WATER INJECTED

21

IO mg

2 0 mg 30mg SODIUM SALICYLATE INJECTED

Figure 3. The effect of sodium salicylate injection into the yolk on day 1 on subsequent in vitro incorporation of 35 S-sulfate (day 3 ) by isolated chick embryo hearts.

INTO

22

CONGENITAL

HEART

DISEASE

Preliminary experiments on mouse hearts indicate results similar to those in the chick. Mouse hearts gathered on gestational day 10 and incubated in varying concentrations of sodium salicylate demonstrate a dose-related inhibition of 35S-sulfate incorporation (Figure 4 ) . Incubation in identical concentrations of parahydroxybenzoic acid does not cause any significant inhibition. In vivo administration of sodium salicylate on gestational day 9 results in a demonstrably smaller embryo heart weight on day 10 (Figure 5 ) . This retardation in growth is significantly greater for the heart than for the rest of the embryo. Normal ten-day mouse embryo hearts have been labeled in vitro with 35Ssulfate and the pattern of isotope distribution determined according to the CPC-cellulose column technique. As seen in Table 3, almost all of the acid mucopolysaccharide radioactivity is concentrated in the 0.6M MgCl2 frac-

SODIUM

SALICYLATE

CONCENTRATION mg/100 ml

Figure 4. Effects of varying concentrations of sodium salicylate on in vitro 3r, S-sulfate incorporation by isolated 10-day mouse embryo hearts. Incubation time: 2 hr. Black circles: mean values; vertical bars: range of 2 S. D.

EFFECTS

OF

SODIUM

SALICYLATE

23

16 - ,

12
.g

E 8 S ÜJ

2 z

O iu

Iii

< LÜ i. O o X wE Ui 2 9 2 LÜ ¥

oa: i-

1/5

li.

o z

i u

iÜ ASV^AMER-io

ui o

1

I JL ACIDEMIA

ASVX)

NOREPINEPHRINE

ASV-IO

ACIDEMIA + NOREPINEPHRINE

Figure 37. Average changes in stroke volume (SV 10 ) and mean ejection rate (MER 1 0 ) for all preparations at a LVEDP of 10 cm H 2 0 . No significant change was found in SVj 0 or MER 10 in response to acidemia. White column shows average changes in SV10 consequent to norepinephrine infusion with pH 7.36-7.50. Hatched column indicates average change in SV10 following norepinephrine infusion during acidemia (pH 6.80-6.90). The responses to norepinephrine were unimpaired during acidemia. Vertical bars: S.E.M. (From Talner, Gardner & Downing, 44.)

The mean heart rate was 256 ( ± 10.47 S.E.) beats/min., systemic blood flow was 198.1 ( ± 1 3 . 4 S.E.) ml/kg/min., and systemic resistance was 94.2 ( ± 13.35 S.E.) mm Hg/liter/min. It is evident from Figure 39 that there was little important change in any of the parameters after the first 24 hours of life. The initial arterial pressure of the youngest lamb (49 mm

METABOLIC

AND

REFLEX

INFLUENCES

75

RECORDER

Figure 38. Intact lamb preparation. Lambs are anesthetized, a tracheotomy is performed, and ventilation maintained with a constant volume pump. Systemic blood flow is measured by the indicator dilution method, using indocyanine green dye injected near the right atrium ( I N J . ) . Sampling is done from the abdominal aorta.

Hg) was much lower than the mean value of the others (88 mm Hg). One animal three days of age showed an unexpectedly low systemic flow (87 ml/kg/min.) which persisted throughout 45 indicator dilution curves. With this exception, the range of values for systemic blood flow obtained shortly after anesthesia during spontaneous respiration was quite narrow (166-246 ml/kg/min.). As might be expected, the largest value was in the youngest lamb. The mean value for systemic blood flow obtained under these conditions [198.1 ( ± 13.0 S.E.) ml/kg/min.] is identical with the value reported by Assali, Morris & Beck ( 1 ) for systemic blood flow in the term fetus prior to lung expansion (198 ml/kg/min.). The findings reported by Mahon and coworkers (35) suggest a somewhat greater systemic blood flow in the

76

CONGENITAL INITIAL VALUES

12 L A M B S

HEART

DISEASE

3 5 OBSERVATIONS 100

100 90

90

X

80

80

2 w x O

2 5 W x O

D

cc.

or

1 u

lÄ 1 pH

pH

738

m

7.18

«P o u

CO

1

50

1

-

0

\ o i

75 100 125 TENSION, gm/cm 2

»

150

Figure 82. Tension-velocity relations in variably afterloaded beats, in which end-diastolic volume was constant. A: Total tension in grams at the internal equator is shown during the control state (white symbols) and during the infusion of norepinephrine (black symbols). Since the rate of extension of the series elastic is zero at peak tension, at this point V C E = V C F . B: Illustrates the same relations, but tension is expressed as wall stress in g/cm 2 . V,.K: Velocity of the contractile elements; V r K : velocity of the circumferential fibers.

CONTRACTION

MECHANICS

OF I N T A C T

HEART

157

30 6

a> in

s £ u

0

0

1000

2000

3000

TENSION gm. Figure 83. Tension-velocity relations obtained during the course of single isovolumic contractions. The velocity of the contractile elements is plotted from the time of maximum contractile element velocity to maximum isometric tension, a hyperbolic relation being apparent until near peak tension when the tension-velocity relation departs from the hyperbolic curve; the latter effect is probably due to decay of active state. The three curves were obtained with progressively increasing left ventricular end-diastolic pressures (LVEDP) and volumes; it is apparent that the maximum isometric tension (P 0 ) is increased as end-diastolic volume is augmented; however, no obvious change occurs in the extrapolation of the curves to zero velocity or V max .

state without changing Vmax ( 2 ) . Further, this relation was shown to be subject to quantification; thus, a relatively narrow range of force-velocity and length-tension curves were shown to apply in the normal, closed-chest sedated animal (24) and to differ from those in chronically hyper- and hypothyroid animals (22). The application of the principles of muscle mechanics to the analysis of ejecting beats has provided considerable insight into the manner in which changes in inotropic state and in mechanical loading conditions alter cardiac function. In acute experimental heart failure, it was shown that despite a compensatory increase in resting fiber length, which resulted in an unchanged or augmented Po, Vm,« and the velocity and extent of fiber shortening were depressed (12). It also was demonstrated that loading conditions

158

CONGENITAL

HEART

DISEASE

can influence cardiac performance independently of changes in inotropic state. Although it was shown in previous studies (13) that sudden increases or decreases in afterload alone profoundly diminished and augmented, respectively, the stroke volume and extent of fiber shortening, the effects produced by mechanical valvular lesions had not been analyzed in these terms. Therefore, the mechanical influence of altered afterload during the steady state were analyzed by inducing acute experimental aortic and mitral regurgitation (25). In these studies, large changes in the speed and extent of fiber and CE shortening during ejection were observed when no change in the basic contractility of the heart was evident from the force-velocity relations during isovolumic beats. In mitral regurgitation, for example, the low impedance pathway to the left atrium permitted effective unloading of the myocardial fibers during ejection, allowed a more rapid and more extensive shortening of the contractile elements and myocardial fibers (25), and thereby enhanced the overall efficiency of contraction. It is useful to place the analysis of isovolumic and ejecting beats into a three-dimensional structure. This format (5, 14, 19) allows integration of the isovolumic force-velocity relation, the isovolumic length-tension relation, and the characteristics of fiber shortening during ejection (Figure 84). Within this framework of force, velocity and fiber length it is then possible to predict the effects on the intact left ventricle of altered fiber length, altered afterload, and changes in the inotropic state (Figure 84) (14). In this model, the length-tension relation is represented in the horizontal plane and shares a common axis with the force- (or tension-) velocity relation represented on the posterior, vertical plane. Changes in resting fiber length alter the starting point of a given contraction on the length axis, and ejection then occurs within a framework provided by the force-velocity and lengthtension curves (19). A positive inotropic influence, such as norepinephrine, shifts both the force-velocity and length-tension relations (Figure 84). Therefore, the velocity of the contractile elements is faster at any tension during isovolumic contraction; likewise, throughout ejection at a similar afterload or tension, the velocity of fiber shortening is more rapid than control, and the extent of fiber shortening is augmented. This format provides a quantitative means of comparing contractions during such an alteration in inotropic state, and also permits understanding of the net effect which results when concomitant changes in afterload and/or fiber length occur (12). Further refinements and validation of the techniques and assumptions upon which the investigations outlined above are based should be forthcoming, and will undoubtedly expand their usefulness. For example, whether or not changes in the SEC or in the viscous components (10, 20) of the intact heart occur during chronic heart failure remains unknown at present. However, it appears that acute inotropic influences do not change the characteristics of the SEC (18), and recent investigations in isolated cardiac muscle indicate that the chronic influences of hyperthyroidism and hypertrophy do

CONTRACTION

MECHANICS

OF I N T A C T

HEART

159

Figure 84. Three-dimensional diagram in which the data obtained in isovolumic and ejecting beats are combined. The relation between contractile element velocity (vertical axis) and tension (right horizontal axis) for a control isovolumic beat, and the relation during norepinephrine infusion (white triangles lying in the right vertical plane) show the characteristic symmetrical shift of the force-velocity relation upward and to the right, both maximum tension (from D to C) and V m a x (A to B) being augmented. The ejecting beat (shortening being represented by the left horizontal axis) during the control state (black circles) contracts down the isovolumic force-velocity relation until the onset of ejection. It then shortens along the circumference (length) axis to G, which represents a point on the isovolumic length-tension curve (solid line G-D on the horizontal plane). In the ejecting beat during norepinephrine infusion (black triangles), the velocity of the contractile elements (V C E ) is greater during isovolumic contraction; at the onset of ejection ( E ) the velocity of the circumferential fibers is faster, the circumference shortens more rapidly throughout ejection, and the extent of shortening is greater (H) than in the control contraction; H represents a point close to the isovolumic length-tension relation (solid line C-H on the horizontal plane), which is shifted by norepinephrine infusion. (From Taylor, Covell & Ross, 23.)

not modify the SEC appreciably (10). The influence of ventricular shape on mechanical performance has not yet been well defined, and it may be anticipated that biplane cineangiography, employed in conjunction with the present techniques, will allow further characterization of this factor. The important question of the manner in which stress is distributed across the ventricular wall remains unresolved, although present equations probably reflect mean wall stress with relative accuracy (24). Other problems of importance relative to tension development, such as the instantaneous variations in wall thickness during contraction, have recently received attention ( 4 ) , and the geometry of contraction relative to changes in sarcomere length during diastole and systole have been examined (15, 21). It is planned to extend the latter studies to an analysis of fiber bundle direction and sarcomere distribution across the ventricular wall. Although the application of principles derived in isolated muscle to the analysis of the contraction of the intact heart has been relatively recent, this approach has already clarified the manner in which mechanical influences can affect contraction independently of

CONGENITAL

160

HEART

DISEASE

changes in inotropic state, and it seems established that it allows analysis of cardiac contraction in the intact animal in a reproducible and quantitative manner. Therefore, it may be anticipated that these approaches will prove highly useful in patients for identifying and quantifying the effects of a variety of congenital and acquired mechanical cardiac lesions as well as primary diseases of the myocardium. REFERENCES 1. 2.

3.

4.

5. 6. 7. 8. 9.

and MOMMAERTS, W . F. H. M., A study of inotropic mechanisms in the papillary muscle preparation. J. Gen. Physiol., 1959, 42: 533551. COVELL, J. W., Ross, J., JR., SONNENBLICK, E. H., and BRAUNWALD, E., Comparison of the force-velocity relation and the ventricular function curve as measures of the contractile state of the intact heart. Circ. Res., 1966, 19: 364-372. COVELL, J. W., TAYLOR, R. R., and Ross, J., JR., Series elasticity in the intact left ventricle determined by a quick release technique. Fed. Proc., 1967, 26: 382. FEIGL, E. O., and F R Y , D. L., Myocardial mural thickness during the cardiac cycle. Circ. Res., 1964, 14: 541-545. FRY, D. L., Discussion of Sonnenblick (17). Fed. Proc., 1962, 21: 991-993. F R Y , D. L., GRIGGS, D. M., JR., and GREENFIELD, J. C., JR., Myocardial mechanics: tension-velocity-length relationships of heart muscle. Circ. Res., 1964, 14: 73-85. H I L L , A. V., The heat of shortening and the dynamic constants of muscle. Proc. Roy. Soc. London B, 1938, 126: 136-195. LEVINE, H. J., and BRITMAN, N. A., Force-velocity relations in the intact dog heart. ]. Clin. Invest., 1964, 43: 1383-1396. PARMLEY, W. W., and SONNENBLICK, E . H., Series elasticity in heart muscle: its relation to contractile element velocity and proposed muscle models. Circ. Res., 1967, 20: 112-123.

ABBOTT, B. C.,

1 0 . PARMLEY, W .

11. 12.

13.

14.

W . , SPANN, J . F . , JR., TAYLOR, R . R . , a n d SONNENBLICK, E .

H.,

The series elasticity of cardiac muscle in hyperthyroidism, ventricular hypertrophy, and heart failure. Proc. Soc. Exp. Biol. Med., 1968, 127: 606-609. PODOLSKY, R. J., The chemical thermodynamics and molecular mechanism of muscular contraction. Ann. N.Y. Acad. Sci., 1959, 72: 522-537. Ross, J., JR., COVELL, J. W., and SONNENBLICK, E . H., The mechanics of left ventricular contraction in the acute experimental cardiac failure. J. Clin. Invest., 1967, 46: 299-312. Ross, J., JR., COVELL, J. W., SONNENBLICK, E . H., and BRAUNWALD, E., Contractile state of the heart characterized by force-velocity relations in variably afterloaded and isovolumic beats. Circ. Res., 1966, 18: 149-163. Ross, J., JR., COVELL, J. W., SONNENBLICK, E. H., and TAYLOR, R. R., Contractile state of the in situ heart characterized by tension-velocity-length relations. In: Factors Influencing Myocardial Contractility (R. D. Tanz, F. Kavaler and J. Roberts, Eds.). Academic Press, New York, 1967: 189-197,

CONTRACTION 15.

16. 17. 18. 19. 20.

MECHANICS

OF

INTACT

HEART

161

Ross, J . , JR., SONNENBLICK, E . H . , COVELL, J . W . , KAISER, G . A . , and SPIRO, D . , The architecture of the heart in systole and diastole; technique of rapid fixation and analysis of left ventricular geometry. Circ. Res., 1967, 21: 409-421. SONNENBLICK, E. H., Force-velocity relations in mammalian heart muscle. Am. J. Physiol., 1962, 202: 931-939. , Implications of muscle mechanics in the heart. Fed. Proc., 1962, 21: 975-990. , Series elastic and contractile elements in heart muscle: changes in muscle length. Am. J. Physiol, 1964, 207: 1330-1338. , Instantaneous force-velocity-length determinants in the contraction of heart muscle. Circ. Res., 1965, 16: 441-451. SONNENBLICK, E. H . , Ross, J . , JR., COVELL, J . W., and BRAUNWALD, E., Alterations in resting length-tension relations of cardiac muscle induced by changes in contractile force. Circ. Res., 1966,19: 980-988.

2 1 . SONNENBLICK, E . H . , ROSS, J . , JR., COVELL, J . W . , SPOTNITZ, H . M . , a n d SPIRO,

D., The ultrastructure of the heart in systole and diastole; changes in sarcomere length. Circ. Res., 1967, 21: 423-431. 2 2 . TAYLOR, R. R., COVELL, J. W . , and Ross, J., JR., Influence of the thyroid state on left ventricular tension-velocity relations in the intact, sedated dog. J. Clin. Invest., 1969, 48: 775-784. 23. , Volume-tension diagrams of ejecting and isovolumic contractions in left ventricle. Am. J. Physiol, 1969,216:1097-1102. 24. TAYLOR, R. R., Ross, J . , JR., COVELL, J . W., and SONNENBLICK, E. H., A quantitative analysis of left ventricular myocardial function in the intact, sedated dog. Circ. Res., 1967, 21: 99-115. 2 5 . URSCHEL, C . W . , COVELL, J . W . , SONNENBLICK, E . H . , Ross, J . , JR., and BRAUNWALD, E., Myocardial mechanics in aortic and mitral valvular regurgitation: the concept of instantaneous impedance as a determinant of performance of the intact heart. J. Clin. Invest., 1968, 47: 867-883.

DETERMINANTS OF VENTRICULAR FUNCTION* JERE H. MITCHELLt and CHARLES B. MULLINS The Pauline and Adolph Weinberger Laboratory for Cardiovascular Research Department of Internal Medicine University of Texas Southwestern Medical School Dallas, Texas

Much work has been done recently applying to cardiac muscle Hill's concepts derived for skeletal muscle mechanics (1,4, 26,41, 4 2 ) , and these new concepts of cardiac muscle mechanics have been applied to the intact left ventricle (13, 21, 3 3 ) . This application of skeletal muscle concepts to cardiac muscle function represents a major advance in our basic understanding of the subject. However, there is a long tradition of considering the left ventricle as a compression pump, and useful information has also been obtained from this approach ( 5 , 7 , 1 2 , 28, 32, 34, 36-39). There are two purposes to this presentation: To review the principles involved in evaluating ventricular performance in terms of a compression pump, and to discuss some of the major determinants of ventricular function when it is examined by this approach. One of the earliest observations in regard to the pump function of the ventricle was that a distended ventricle ejects a larger volume of blood with each stroke than does a more empty one. As early as 1740, Stephen Hales ( 1 7 ) , while studying the effect of blood loss on the pulse rate and blood pressure of a mare, found that . . the violent straining to get loose . . . by the activity of most of her muscles caused an increased venous return to the heart, . . . which must therefore throw out more at each pulsation." Probably the first systematic study of the function of the ventricle was performed in frogs by Roy in 1879 ( 3 4 ) . His experiments demonstrated that the work of the ventricle could be varied by its degree of filling when outflow resistance and heart rate were held constant. From this study he concluded that the work of the ventricle "is capable of being varied within wide limits by variations in the venous pressure, and more so still by variations in the force of auricular contraction." In 1895, Frank ( 1 2 ) published a more thorough study of the frog heart. He found that the tension developed •Research supported by grants from the U.S. Public Health Service HE 0 7 7 1 7 ) and the Dallas Heart Association, f Established Investigator, American Heart Association. 163

(HE

06296

and

164

CONGENITAL

HEART

DISEASE

in an isovolumically contracting ventricle was proportional to the initial or end-diastolic tension. In Frank's experiments, the initial length and the initial tension (pressure) were proportional; thus the increased force of contraction might be due either to increased diastolic fiber length or to increased diastolic pressure. Starling (28) carried out similar studies in a dog heart-lung preparation and concluded, "The output of the heart is a function of its filling, the energy of its contraction depends on the state of the dilatation of the heart's cavities." In the Linacre lecture (45), Starling stated his law in its simplest and most general form as follows: "The law of the heart is thus the same as the law of muscular tissue generally, that the energy of contraction, however measured, is a function of the length of the muscle fibre." This concept is now generally referred to as the Frank-Starling principle and forms the foundation for the evaluation of ventricular function in terms of a compression pump. As has been clearly pointed out by Mommaerts & Langer (26), this approach follows directly from extrapolation of the length-tension relation of cardiac muscle. They state that the ventricular function curve concept can be logically derived from "the considerations that (a) the ventricular function curve can be derived from the length-tension or volume-pressure diagram by integration, and (b) in a stronger muscle the length-tension curve is situated higher, and so gives rise to a higher situated ventricular function curve" (26). The concept involved in a ventricular function curve is shown in Figure 85. In this approach, an estimate of the "energy of ventricular contraction, however measured," probably better termed the mechanical activity of the left ventricle, is related to an estimate of the end-diastolic "fiber length" of the ventricle. Various measurements have been used to quantitate the mechanical activity of the ventricle. Cardiac output or stroke volume was used by Starling (28). The amount of work performed by the ventricle with each beat, or the stroke work, has been the most often used estimate of ventricular action (5, 7, 12, 28, 32, 34, 36-39). This value is most accurately calculated from instantaneous pressure-volume measurements of the ventricle, but can be adequately approximated by using mean values of stroke volume and ejection pressure (8). Stroke power has been shown to be a more discriminating estimate of the mechanical activity of the ventricle, since it includes a rate component (25). Stroke power is calculated by dividing the stroke work by the duration of ejection; it represents the mean rate of performing work each beat. In view of findings in papillary muscle preparations (1, 42), it has been suggested that the peak or maximal power production reached during the period of ventricular ejection might be a more critical estimate of ventricular action. Various measurements have also been used to indicate the end-diastolic "fiber length" of the ventricle. Because of the complex arrangement of muscle fibers in the wall of the ventricle, it is not possible to measure this quan-

VENTRICULAK

VENTRICULAR

FUNCTION

DETERMINANTS

165

ACTION

1. S t r o k e volume 2 . Stroke work 3 . Stroke power 4 . P e a k power

END - DIASTOLIC " F I B E R LENGTH" OF T H E V E N T R I C L E 1. M e a n a t r i a l

pressure

2. Ventricular end-diastolic

pressure

3 . Ventricular e n d - d i a s t o l i c

volume

4 . Ventricular e n d - d i a s t o l i c

area

Figure 85. Ventricular function curve concept. For each beat an estimate of the mechanical activity of the ventricle (ventricular action) is related to an index of the enddiastolic fiber length of the ventricle.

tity as it is in skeletal muscle or in cardiac papillary muscle preparations. In earlier investigations, the venous pressure or the height of the venous reservoir was regarded as the filling pressure, which determined the end-diastolic fiber length of the ventricle (28, 34). Mean atrial pressure was once used as an estimate of the fiber length, as it was assumed that it was an accurate reflection of left ventricular end-diastolic pressure (36). It is now clear, however, that this assumption is not valid and that left ventricular end-diastolic pressure must be measured directly (23, 37, 38). Recently, left ventricular end-diastolic pressure has been the most often used estimate of the end-diastolic fiber length (6, 38). For many years left ventricular end-diastolic volume has been thought to be the most logical estimate of end-diastolic fiber length (12, 28, 34), but the development of methods to measure accurately the volume of the left ventricle has been difficult. Cardiometers were originally used to measure the volume of both ventricles simultaneously (28, 34). More recently, indicator-dilution methods have been employed to determine the left ventricular end-diastolic volume (20, 29). Biplane cineangiocardiography has also been utilized for this measurement (2, 8, 9, 11, 15).

CONGENITAL

166

HEART

DISEASE

Recently, the geometrical changes of a shell of cardiac muscle adjacent to the cavity of the left ventricle have been studied in dogs by determining with biplane cinefluorography the movements of lead beads placed near the cavity of that chamber (24). Both the volume and area of this shell are calculated, and either can be used as an index of the length of the cardiac muscle fibers of which it is composed. The area is probably a better estimate than the volume, since at a constant volume the area, and thereby the degree of extension of the fibers in the shell, can vary with changes in geometrical shape. That is, the area for any given volume will be less if the ventricle is more spherical in shape and will be larger if the ventricle is more ellipsoidal in shape. In this method, six lead beads are used to demarcate the major and two minor axes of an assumed ellipsoidal shell of cardiac muscle adjacent to the cavity of the left ventricle. The anatomic location of these beads and of the three axes is shown in Figure 86. The base bead is sutured just below the left circumflex coronary artery, and the apex bead is sutured to the apical dimple. The anterior, posterior, septal, and lateral beads are each placed near the cavity of the left ventricle through a properly positioned needle. The distance between the base and apex beads is the base-to-apex length ( L i ) , that between the anterior and posterior beads is the anterior-to-posterior length ( L 2 ) , and that between the septal and lateral beads is the septal-to-lateral length ( L 3 ) . The volume of this cardiac muscle shell ( L V V ) is calculated from these three axes using the formula, LVV

wherea = Li/2,

& = L2/2,

= 4/3trabc

and c = L 3 /2.

It should be noted that this cavity volume of the left ventricle contains the anterior and posterior papillary muscles and the trabeculae carneae; therefore, this volume is not the same as the volume of blood contained in the left ventricle. As previously stated, the volume determined is simply that of a shell of cardiac muscle near the cavity of the left ventricle and is defined by the location of the six beads. However, since the volume of cardiac muscle does not change from the relaxed to the contracted state, a change in volume of this shell represents a change in the volume of blood contained in the left ventricle; for this reason, stroke volume and calculations of work and power can be determined by this method. The area of this same cardiac muscle shell (LVA) is calculated using the formula, LVA

~

2rrab

V

'1 +

(c/by

b/a H+

sin~W V I

1 -

(b/a)2 ib/aY

The movements in space between the three pairs of beads were calculated from biplane cinefluorographic exposures taken on 35 mm film at intervals

VENTRICULAR

FUNCTION

DETERMINANTS

167

Figure 86. Location of beads demarcating axes of ellipsoidal shell of cardiac muscle. (From Mitchell & Mullins, 24.)

of 1/60 second. A pair of simultaneously obtained cinefluorographic exposures in an open-chest dog experiment is shown in Figure 87. A 24 mm steel ball (top of each projection) was placed just above the heart, to be used to calibrate the image size. A catheter tip pressure transducer is seen in the cavity of the left ventricle. The shadow just below the ball is an electromagnetic flowprobe placed around the root of the aorta. Also visible is a pacing electrode and its connecting wires. The base, apex, anterior, and posterior beads (2 mm in diameter), and the septal and lateral beads (1 mm in diameter) are easily recognizable in both projections. From appropriate measurements made between each pair of beads in these two projections, the spatial lengths of the three axes were determined, and then the volume and area of this ellipsoidal shell of cardiac muscle adjacent to the cavity of the left ventricle were calculated. The volume and area calculations were correlated temporally with simultaneously obtained continuous measurements of aortic

CONGENITAL

HEART

DISEASE

Figure 87. Biplane cinefluorographic exposures in an open chest dog study. Left: Anterior-posterior projection. Right: Lateral projection. Image-size calibrated by comparison with a 24 mm steel ball placed just above the heart. See text.

pressure, left ventricular pressure, and aortic flow by signal marks which occurred on the recording each time a pair of X-ray exposures was taken. A demonstration of the Frank-Starling principle utilizing the bead method for volume and area is shown in Figure 88. These data were obtained in an open-chest dog experiment in which aortic pressure and heart rate were held constant and venous return was varied. In both panels, left ventricular stroke work in gram-meters is plotted on the ordinate and is used as an estimate of the mechanical activity of the ventricle. In the left panel the volume in cm3 of a shell of cardiac muscle adjacent to the cavity of the left ventricle is used as an index of the end-diastolic fiber length of the ventricle, and is plotted on the abscissa. In the right panel, left ventricular end-diastolic area in cm2 is used instead of volume as an index of end-diastolic fiber length of the left ventricle. These two graphs demonstrate the first type of intrinsic (myogenic) response, or autoregulation of the left ventricle (38, 39). This response enables the ventricle to eject whatever volume it receives. When inflow is increased, the end-diastolic fiber length is increased, and the ventricle contracts more forcefully and ejects a larger stroke volume. The Frank-Starling principle operates on a beat-to-beat basis, and has been termed heterometric autoregulation since it involves a change in end-diastolic fiber length (38, 39).

VENTRICULAR

FUNCTION

DETERMINANTS

169

50

45 LEFT VENTRICULAR STROKE WORK

gm-meters

40

35

j L 55 60 65 70 LEFT VENTRICULAR END-DIASTOLIC IC VOLUME

(cm3)

60 65 LEFT VENTRICULAR AREA

77 00 75 END-DIASTOLIC

(cm2)

Figure 88. Ventricular function curve (Frank-Starling principle). Left: Relation between left ventricular stroke work and end-diastolic volume. Right: Relation between left ventricular stroke work and end-diastolic area.

The great majority of physiological and clinical studies of ventricular function have utilized ventricular function curves relating stroke work or stroke power to the end-diastolic pressure of the ventricle. It is therefore necessary to examine the relation of the filling pressure of the left ventricle, or left ventricular end-diastolic pressure, to both the left ventricular end-diastolic volume and the end-diastolic area. Data to examine this relation were obtained in this same experiment and are shown in Figure 89. In the upper panel of this figure, left ventricular end-diastolic pressure in cm of H 2 0 is plotted on the ordinate, and left ventricular end-diastolic volume in cm3 is plotted on the abscissa; in the lower panel, left ventricular end-diastolic pressure in cm H2O is plotted on the ordinate and left ventricular end-diastolic area in cm2 on the abscissa. At low end-diastolic pressures both curves are flat and almost linear, but at higher end-diastolic pressures the curves begin to rise steeply. Thus, on the initial part of the curves a small increase in ventricular end-diastolic pressure causes a large increase in end-diastolic volume or area, and on the latter portion of the curves a large increase in pressure causes only a small increase in volume or area. If end-diastolic fiber length increases in proportion to either the end-diastolic volume or area, then end-diastolic pressure must bear a nonlinear relationship to the end-diastolic fiber length. The relation between left ventricular stroke work and end-diastolic pressure in this same experiment is shown in Figure 90. At low left ventricular end-diastolic pressures the curve is almost linear and quite steep; this corresponds to the initial portion of either the pressure-volume or pressure-area

170

CONGENITAL

HEART

DISEASE

20 iiJ tr

3s

15

en CM UJ _) „ X 10 CO H< s? 9 -1 Q

55

60

LEFT VENTRICULAR

65

END-DIASTOLIC (cm 3 )

70

VOLUME

20

DCco ico

15

SJ^iioh kid

SI 2 UJ

60

65

75

70

L E F T VENTRICULAR E N D - D I A S T O L I C (cm2)

AREA

Figure 89. Above: Relation between left ventricular end-diastolic pressure and enddiastolic volume. Below: Relation between left ventricular end-diastolic pressure and end-diastolic area.

curve, where small changes in pressure cause large changes in volume or area. At higher left ventricular end-diastolic pressures the curve tends to rise much less steeply; this corresponds to the latter portion of either the pressure-volume or the pressure-area curve, where a large increase in pressure causes only a small increase in volume or area. Since the normal left ventri-

VENTRICULAR

FUNCTION

DETERMINANTS

171

50

45 LEFT VENTRICULAR STROKE WORK

gm-meters

40

35

30

I ' i i i ' i _L 0 5 10 15 20 LEFT VENTRICULAR END-DIASTOLIC PRESSURE (cmH20)

Figure 90. Ventricular function curve relating left ventricular stroke work to end-diastolic pressure.

cle is usually operating at low filling pressures where stroke work can be markedly altered by small changes in pressure, use of this relation in evaluating ventricular function is less sensitive and less reliable than use of the relation between end-diastolic volume or area and stroke work (6). It has been shown that one of the determinants of ventricular function is the end-diastolic fiber length; this mechanism forms the basis for the ventricular function curve concept of evaluating ventricular performance. Since the great majority of physiological and clinical studies of ventricular function have utilized ventricular function curves relating stroke work or stroke power to end-diastolic pressure, these relations will be used to describe some of the other determinants of ventricular function. As just noted, this approach is somewhat limited, since the end-diastolic pressure is not as reliable or as sensitive an index of fiber length as is the end-diastolic volume or area. In the future, left ventricular end-diastolic area will probably be used as the most accurate estimate of the end-diastolic fiber length. Changes in contractility or inotropism of the left ventricle can be defined by utilizing the ventricular function curve concept (36, 38), as illustrated in Figure 91. The middle curve represents the control condition. A decrease in contractility, or a negative inotropic effect on the ventricle, is represented by a movement of the curve downward and to the right; that is, the ventricle is able to perform less stroke work and less stroke power from any given end-diastolic pressure and presumably fiber length of the ventricle (or, the

172

CONGENITAL

HEART

VENTRICULAR

DISEASE

END-DIASTOLIC cm H 2 0

PRESSURE

Figure 91. T h e use of ventricular function curves to demonstrate changes in contractility. See text.

performance of a given amount of stroke work or stroke power requires a higher end-diastolic pressure and fiber length of the ventricle). An increase in contractility, or a positive inotropic effect on the ventricle, is represented by a movement of the curve upward and to the left; that is, the ventricle is able to perform more stroke work and more stroke power from any given end-diastolic pressure and fiber length of the ventricle (or, the performance of a given amount of stroke work or stroke power does not require as high an end-diastolic pressure). The second type of intrinsic (myogenic) response or autoregulation of the left ventricle occurs after an increase in frequency of contraction or heart rate. In 1871, Bowditch ( 3 ) showed in a frog ventricle that a gradually increasing force of contraction occurred when regular stimuli were applied following a period of rest. Later, this same finding was also demonstrated in the dog ventricle (47). Also, the force of contraction of the ventricle was shown to be a function of the rate of application of regular stimuli (10, 16). When heart rate was abruptly increased in an isolated supported heart preparation and a lower level of stroke work accomplished, there was a subsequent decrease in left ventricular end-diastolic pressure beginning either immediately or after a transient rise (38, 39). This decline in end-diastolic pressure at a constant stroke work indicates a gradually increasing contractility at the higher heart rate. The effect of an increase in heart rate on ventricular function curves when aortic pressure and stroke volume were kept constant (Figure 92) was studied

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in a dog right-heart bypass preparation (25). The relation between left ventricular stroke work in gram-meters and end-diastolic pressure in cm ILO is shown in the left panel; the relation between left ventricular stroke power in gram-meters/second and end-diastolic pressure in cm H2O appears in the right panel. The left panel shows that the stroke work performed from any given end-diastolic pressure was the same at both the control and the increased heart rates, while the right panel indicates that the stroke power from any given end-diastolic pressure was increased at the higher heart rate. The mechanism shown in Figure 92 enables the ventricle to perform the same stroke work and an increased stroke power at a higher heart rate with-

cm H2O Figure 92. The effect of heart rate on ventricular function curves. Left: Relation between left ventricular stroke work and end-diastolic pressure. Right: Relation between left ventricular stroke power and end-diastolic pressure. See text.

out utilizing heterometric autoregulation (Frank-Starling principle) more than briefly. This intrinsic or myogenic response has been termed frequency or heart-rate induced homeometric autoregulation, since the intrinsic increase in contractility tends to maintain constant left ventricular end-diastolic fiber length (38,39). The third type of intrinsic response or autoregulation of the left ventricle occurs after an increase in its tension development (38, 39). This phenomenon must be separated from the increased stroke work performed because of an increase in afterload (38, 43) since, as has been clearly stated, an increase in contractility has occurred only "when, from any given end-diastolic pressure or fiber length, the ventricle produces more external stroke work and external stroke power . . ." if ". . . specifically excluded is any in(38). Ventriccreased work that may be done as the result of afterload . . ular function curves obtained at a constant heart rate by varying stroke volume at two levels of aortic resistance are shown in Figure 93. The stroke work performed from any given end-diastolic pressure was increased at the

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CONTROL INCREASED AORTIC RESISTANCE

LEFT VENTRICULAR STROKE

WORK

gm - meters

LEFT

VENTRICULAR

END-DIASTOLIC

PRESSURE

cm H2O Figure 93. The effect of aortic resistance on the ventricular function curve relating left ventricular stroke work to end-diastolic pressure. See text.

higher aortic resistance. The increase in contractility demonstrated in this figure is to some degree more apparent than real. At least three factors are contributing to the changes that are seen. The first is an increase in the amount of stroke work performed because of the increase in afterload (38, 43). The second is a decreased diastolic compliance that has been shown to occur after an increased force of ventricular contractions (14, 44) and would cause a lower end-diastolic pressure for any given end-diastolic volume or area. The third is an intrinsic increase in contractility of the left ventricle which occurs after an increase in its tension development (38, 39). The relative magnitude of each of these factors in producing the changes seen in Figure 93 is not known. The increase in contractility that occurs after an increase in the tension development of the ventricle is of interest. In 1912, Anrep (46) noted that after an abrupt increase in aortic pressure the biventricular end-diastolic volumes increase as the stroke work rises and then, while stroke work remains at the elevated level, the biventricular end-diastolic volumes decrease toward

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the control value. This effect was later ascribed to the increased coronary flow which resulted from the increase in aortic pressure (28). In 1959, Rosenblueth and coworkers (30, 31), inferring constant coronary flow since coronary perfusion pressure was held constant, were able to demonstrate the Anrep effect in the isolated right ventricle when pulmonary artery pressure was increased. The effect of a sudden increase in aortic resistance on the left ventricle when left coronary flow was kept constant has also been studied in the isolated supported dog heart preparation (38, 39). When flow into the left atrium and heart rate were held constant and aortic pressure was abruptly increased, left ventricular end-diastolic pressure increased as the stroke work increased (constant stroke volume and increasing left ventricular pressure during ejection). However, after this initial rise left ventricular end-diastolic pressure decreased while stroke work remained constant at the elevated level. Part of the decrease in left ventricular end-diastolic pressure during this phase is the result of the decreased diastolic compliance that has been shown to occur after an increased strength of contraction (14, 44). However, this response has also been observed when left ventricular volume (27), left ventricular myocardial segment length (22), and left ventricular length and circumference (14) were used as estimates of fiber length. Thus the entire fall of end-diastolic pressure cannot be caused solely by a decreased diastolic compliance. This increase in contractility which occurs after an increase in tension development enables the ventricle to eject the same stroke volume against an increased aortic resistance without an increase in end-diastolic fiber length or utilization of the Frank-Starling mechanism (heterometric autoregulation). This intrinsic or myogenic response has been termed tension-induced homeometric autoregulation, since the intrinsic increase in contractility tends to maintain constant left ventricular end-diastolic fiber length (38, 39). It should be emphasized, however, that an analogous type response has not been reported from studies on papillary muscle preparations. The discrepancy between the behavior of the intact left ventricle and a papillary muscle preparation is not clear and at the present time is being actively studied by many investigators. An examination of three intrinsic (myogenic) mechanisms which determine ventricular function has now been made. It is clear also that varying aortic resistance can affect the relation between the ventricular stroke work and end-diastolic pressure without necessarily causing an increase in contractility (38, 43). For these reasons it is necessary to control heart rate and aortic resistance when other factors which may affect the contractility of the left ventricle are being examined. It has been shown that other factors, both neurogenic and humoral, can determine ventricular function; these have been termed extrinsic influences (38, 39). An example of an extrinsic influence is shown in Figure 94, which illustrates the effect of increased cardiac sympathetic nerve activity or nor-

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epinephrine infusion on ventricular function curves when heart rate and aortic pressure are held constant. There is an increase in the amount of stroke work produced by the left ventricle from any given end-diastolic pressure, and a greater increase in the amount of stroke power produced by the left ventricle from any given end-diastolic pressure. It has also been shown by utilizing the bead method for volume and area that the amount of stroke work and amount of stroke power produced from any given end-diastolic volume or area is also increased by norepinephrine infusion. ° Thus, increased sympathetic activity increases the contractility of the left ventricle. However, it has been suggested that norepinephrine infusion increases the diastolic compliance of the left ventricle (19, 35, 40), a change which would

cm H2O

Figure 94. The effect of increased cardiac sympathetic nerve activity on ventricular function curves when heart rate and aortic pressure are held constant. Left: Relation between left ventricular stroke work and end-diastolic pressure. Right: Relation between left ventricular stroke power and end-diastolic pressure.

account in part for the fall in end-diastolic pressure. Also, Hawthorne & Ison (18) have found that a change in end-diastolic shape but not in volume occurs after the administration of norepinephrine. These possibilities are currently being investigated with the volume and area method which utilizes beads implanted near the endocardium. A summary of the determinants of ventricular function is shown in Table 11. These determinants are divided into intrinsic or myogenic mechanisms and extrinsic influences. Under intrinsic or myogenic mechanisms it has been shown that the left ventricle utilizes three types of autoregulation. The first type occurs immediately after an increase in end-diastolic fiber length of the ventricle and has been termed the Frank-Starling principle, or heterometric autoregulation since it involves a change in end-diastolic fiber length; 0

J. H. Mitchell and C. B. Mullins, unpublished observations.

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T A B L E 11 S U M M A R Y OF T H E D E T E R M I N A N T S OF V E N T R I C U L A R

FUNCTION

I. Intrinsic (Myogenic) Mechanisms—Autoregulation A. Heterometric autoregulation (Frank-Starling principle) B . Frequency (heart rate)—induced homeometric autoregulation C. Tension-induced homeometric autoregulation (Anrep effect)

(Bowditch

effect)

I I . Extrinsic Influences A. Neurogenic B . Humoral

this mechanism occurs on a beat-to-beat basis and allows the ventricle to eject whatever volume it receives. The second type occurs after an increase in heart rate, and has been termed frequency-induced homeometric autoregulation or the Bowditch effect; this mechanism takes several beats to develop fully, and the intrinsic increase in contractility tends to maintain enddiastolic fiber length constant while the ventricle performs the same stroke work and an increased stroke power. The third type occurs after an increase in tension development, and has been termed tension-induced homeometric autoregulation or the Anrep effect; this mechanism also takes several beats to develop fully and it tends to maintain end-diastolic fiber length constant while the ventricle ejects the same stroke volume against an elevated aortic resistance. As extrinsic influences, both neurogenic and humoral factors can affect ventricular function; this is exemplified by increased cardiac sympathetic nerve activity or the administration of norepinephrine, which has been shown to increase the amount of stroke work and stroke power produced from any given ventricular end-diastolic pressure or fiber length.

Summary

The Frank-Starling principle, which states that the mechanical activity of the left ventricle is related to the end-diastolic fiber length, forms the basis for the evaluation of ventricular function in terms of a compression pump. Although probably the most logical estimate of the end-diastolic fiber length would be either the volume or the area of a shell of cardiac muscle adjacent to the cavity of the left ventricle, the great majority of physiological and clinical investigations have utilized ventricular function curves relating stroke work or stroke power to end-diastolic pressure of the ventricle. This is a less desirable approach, since the end-diastolic pressure is not as sensitive or as reliable an index of fiber length. It is also important that heart rate and aortic resistance be controlled when the effect of other interventions (extrinsic influences) is being examined. But even though this approach to the study of ventricular performance has certain definite limitations, it has yielded useful and important information about the determinants of ventricular function.

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and M O M M A E R T S , W . F . H . M . , A study of inotropic mechanisms in the papillary muscle preparation. J. Gen. Physiol., 1959, 42: 533551. ARVIDSSON, H., Angiocardiographic observations in mitral disease; with special reference to volume variations in the left atrium. Acta Radiol. (Stockholm), 1958, Suppl. 158. BOWDITCH, H. P., Ueber die Eigenthiimlichkeiten der Reizbarkeit, welche die Muskelfasern des Herzens zeigen. Ber. Konigl. Sachs. Ges. Wiss., 1871, 23 : 652-689. BRADY, A. J . , Time and displacement dependence of cardiac contractility: problems in defining the active state and force-velocity relations. Fed. Proc., 1965, 24: 1410-1420. BRAUNWALD, E . , F R A H M , C . J . , and Ross, J . , JR., Studies on Starling's law of the heart. V. Left ventricular function in man. /. Clin. Invest., 1961, 40: 1882-1890. BRAUNWALD, E., and Ross, J . , JR., Editorial: The ventricular end-diastolic pressure; appraisal of its value in the recognition of ventricular failure in man. Am. J. Med., 1963, 34: 147-150. BURCH, G . E . , R A Y , C. T . , and CRONVICH, J . A . , Certain mechanical peculiarities of the human cardiac pump in normal and diseased states. Circulation, 1952, 5 : 504-513. CHAPMAN, C . B . , BAKER, O., and M I T C H E L L , J . H., Left ventricular function at rest and during exercise. J. Clin. Invest., 1959, 38: 1202-1213. CHAPMAN, C . B . , BAKER, O . , REYNOLDS, J . , and B O N T E , F . J . , Use of biplane cinefluorography for the measurement of ventricular volume. Circulation, 1958, 18: 1105-1117. D A L E , A. S., The relation between amplitude of contraction and rate of rhythm in the mammalian ventricle. (Including interpretation of the apparent indirect action of the vagus on amplitude of ventricular contraction. ) /. Physiol. (London), 1930, 70: 455-473.

1 . ABBOTT, B . C . ,

2. 3.

4.

5.

6.

7.

8. 9.

10.

1 1 . DODGE, H . T . , SANDLER, H . , B A L L E W , D . W . , a n d LORD, J . D . , J R . , T h e

use

of biplane angiocardiography for the measurement of left ventricular volume in man. Am. Heart J., 1960, 60: 762-776. 12. FRANK, O., Zur Dynamik des Herzmuskels. Zschr. Biol., 1895, 3 2 : 370-437. (Transl.: Am. Heart J., 1959,58: 282-317; 467-478.) 13. F R Y , D . L . , GRIGGS, D . M., JH., and GREENFIELD, J . C., JR., Myocardial mechanics: tension-velocity-length relationships of heart muscle. Circ. Res., 1964, 14: 73-85. 1 4 . G I L M O R E , J . P . , CINGOLANI, H . E . , TAYLOR, R . R . , a n d MCDONALD, R . H . , J R . ,

Physical factors and cardiac adaptation. Am. J. Physiol., 1966, 211: 12191226. 1 5 . G R I B B E , P . , HIRVONEN, L . , LIND, J . , and W E G E L I U S , C., Cineangiocardiographic recordings of the cyclic changes in volume of the left ventricle. Cardiologia, 1959, 34: 348-366. 16. H A J D U , S., Mechanism of staircase and contracture in ventricular muscle. Am. J. Physiol, 1953, 174: 371-380.

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Statical Essays: Containing Haemastaticks; or, an Account of Some Hydraulick and Hydrostatical Experiments Made on the Blood and Blood-Vessels of Animals, 2nd ed. W. Innys, London, 1740. (Also: Hafner, New York, 1964.) HAWTHORNE, E. W., and ISON, E. L., Effects of sympatheticomimetic amines and adrenergic blocking agents on myocardial function. In: Shock and Hypotension; Pathogenesis and Treatment (L. C. Mills and J. H. Moyer, Eds.). Grune & Stratton, New York, 1965: 45-62. HEFNER, L . L . , COGHLAN, H . C . , JONES, W . B . , and REEVES, T . J . , Distensibility of the dog left ventricle. Am. J. Physiol, 1961, 201: 97-101. HOLT, J. P., Estimation of the residual volume of the ventricle of the dog's heart by two indicator dilution technics. Cir. Res., 1956, 4: 187-195. LEVINE, H. J., and BRITMAN, N. A., Force-velocity relations in the intact dog heart. ]. Clin. Invest., 1964, 43: 1383-1396. LEVY, M. N., IMPERIAL, E. S., and ZIESKE, H . , JR., Ventricular response to increased outflow resistance in absence of elevated intraventricular enddiastolic pressure. Circ. Res., 1963, 12: 107-117. MITCHELL, J. H., GILMORE, J. P., and SARNOFF, S. J., The transport function of the atrium; factors influencing the relation between mean left atrial pressure and left ventricular end diastolic pressure. Am. J. Cardiol., 1962, 9 : 237-247. MITCHELL, J . H., and MULLINS, C . B . , Dimensional analysis of left ventricular function. In: Factors Influencing Myocardial Contractility (R. D. Tanz, F. Kavaler and J. Roberts, Eds.). Academic Press, New York, 1967: 177-178. MITCHELL, J . H . , WALLACE, A . G . , and SKINNER, N . S., JR., Intrinsic effects of heart rate on left ventricular performance. Am. J. Physiol., 1963, 205: 41-48. MOMMAERTS, W. F. H. M . , and LANGER, G. A., Fundamental concepts of cardiac dynamics and energetics. Ann. Rev. Med., 1963, 14 : 261-296. MÜLLER, E . A., Die Anpassung des Herzvolumens an den Aortendruck. Pflüger Arch, ges Physiol, 1938, 241: 427-438. PATTERSON, S. W . , PIPER, H . , and STARLING, E . H . , The regulation of the heart beat. }. Physiol. (London), 1914, 48: 465-513. RAPAPORT, E., WIEGAND, B . D., and BRISTOW, J. D., Estimation of left ventricular residual volume in the dog by a thermodilution method. Circ. Res., 1962, 11: 803-810. ROSENBLUETH, A . , ALANÍS, J., LÓPEZ, E . , and RUBIO, R . , The adaptation of ventricular muscle to different circulatory conditions. Arch. Int. Physiol., 1959, 67: 358-373. ROSENBLUETH, A . , ALANÍS, J., RUBIO, R . , and LÓPEZ, E . , The two staircase phenomena. Arch. Int. Physiol, 1959, 67: 374-383. Ross, J . , JR., and BRAUNWALD, E., The study of left ventricular function in man by increasing resistance to ventricular ejection with angiotensin. Circulation, 1964, 29: 739-749. Ross, J . , JR., COVELL, J . W., SONNENBLICK, E. H . , and BRAUNWALD, E., Contractile state of the heart characterized by force-velocity relations in variably afterloaded and isovolumic beats. Circ. Res., 1966, 18: 149-163.

1 7 . HALES, S.,

18.

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34. ROY, C. S., On the influences which modify the work of the heart. J. Physiol. (London), 1879, 1: 452-496. 35. R U S H M E R , R . F., Pressure-circumference relations of left ventricle. Am. J. Physiol, 1956, 186: 115-121. 3 6 . S A R N O F F , S. J . , and B E R G L U N D , E . , Ventricular function. I . Starling's law of the heart studied by means of simultaneous right and left ventricular function curves in the dog. Circulation, 1954, 9: 706-718. 37.

SARNOFF, S. J . , BROCKMAN, S. K . , G I L M O R E , J . P . , LINDEN, R . J . , a n d MITCHELL,

J. H., Regulation of ventricular contraction; influence of cardiac sympathetic and vagal nerve stimulation on atrial and ventricular dynamics. Circ. Res., 1960, 8: 1108-1122. 38. S A R N O F F , S . J., and M I T C H E L L , J. H., The control of the function of the heart. In: Handbook of Physiology; Circulation 1(2). (W. F. Hamilton, Ed.). American Physiological Society, Washington, D.C., 1962 : 489-532. 39.

SARNOFF,

S.

J.,

MITCHELL,

J.

H.,

GILMORE,

J.

P.,

and

REMENSNYDER,

J.

P.,

Homeometric autoregulation in the heart. Circ. Res., 1960, 8: 1077-1091. 4 0 . SCHERLAC, B . J . , B A R T E L S T O N E , H . J . , W Y T E , S . R . , and H O F F M A N , B . F . , Variable diastolic ventricular compliance: a general property of mammalian cardiac muscle. Nature (London), 1966, 209: 1246-1248. 41. S O N N E N R L I C K , E. H., Implications of muscle mechanics in the heart. Fed. Proc., 1962, 21: 975-990. 42. , Determinants of active state in heart muscle: force, velocity, instantaneous muscle length, time. Fed. Proc., 1965, 24: 1396-1409. 4 3 . S O N N E N R L I C K , E . H., and D O W N I N G , S . E . , Afterload as a primary determinant of ventricular performance. Am. J. Physiol., 1963, 204 : 604-610. 4 4 . S O N N E N R L I C K , E . H . , R O S S , J . J R . , C O V E L L , J . W . , and B R A U N W A L D , E . , Alterations in resting length-tension relations of cardiac muscle induced by changes in contractile force. Circ. Res., 1966, 19: 980-988. 45. S T A R L I N G , E. H., The Linacre Lecture on the Law of the Heart. Longmans, Green; London, 1918. [Also in: Starling on the Heart (C. B. Chapman and J. H. Mitchell), Dawsons, London, 1965: 119-147.] 4 6 . VON A N R E P , G . , On the part played by the suprarenals in the normal vascular reactions of the body. /. Physiol. (London), 1912, 45: 307-317. 4 7 . W O O D W O R T H , R. S . , Maximal contraction, "staircase" contraction, refractory period, and compensatory pause, of the heart. Am. J. Physiol., 1902, 8: 213-249.

PANEL DISCUSSION Victor E. Hall, CHAIRMAN, Allan J. Brady, Glenn A. Langer, Jere H. Mitchell, Wilfried F. H. M. Mommaerts and Edmund H. Sonnenblick Hall: As Dr. Langer has not previously spoken, I wonder if he would care to make any remarks. Langer: Over the last few years we have been interested in the ionic control of contractility, and I would like to make a general statement to which we have as yet found no exceptions, namely the importance of the calcium ion as an intermediary in all of the inotropic mechanisms, that involve increased rate of force development (dP/dt), whether it be the classic Bowditch phenomenon or the inotropism induced by low sodium or high calcium; all of these mechanisms involve an increase in calcium in a certain specific area in the muscle, which at present we think may well be the sarcotubular system in the myocardium. Interestingly enough, those mechanisms which are positively ionotropic but would not meet the definition of increased contractility, such as the classic Starling mechanism and the increased contraction developing under the situations of increased load, do not involve increments in calcium uptake in this specific area of the muscle. Hall: The first question from the floor is directed to Dr. Sonnenblick: "Are there differences in cardiac muscle mechanism between normal and hypertrophic muscle?" Sonnenblick: We are indeed very interested in the effect of hypertrophy on the contractile state of muscle. With Dr. Spann ( 3 ) , we have looked specifically into this problem, using the cat, with variable banding of the pulmonary artery, which will produce about 50 per cent hypertrophy of the right ventricle. With severe banding the animal will progress to classical pulmonary heart failure. Using papillary muscle from the right ventricle in vitro, we have found that hypertrophy alone leads to a progressive decrease in contractility of muscle. This is characterized by a fall in the intrinsic velocity of contraction of the muscle. Although the total force development of the muscle may be normal, the force development per unit of muscle decreases progressively as failure develops, with marked depression of intrinsic velocity of contraction and force development. Further, we have also examined the effects of hypertrophy in skeletal muscle, using the soleus preparation ( 2 ) . Like hypertrophied heart muscle, hypertrophied soleus muscle demonstrates decreased contractility with a decrease in speed of contraction and unit force development. This decrease in the intrinsic speed of contraction is accompanied by a decrease in the myo181

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fibrillar ATPase activity in heart muscle (1). Thus, hypertrophy per se, although serving as a compensatory mechanism, also leads to a decrease in contractility of muscle. Hall: Let us proceed to one of the other questions: "At the ultrastructural level, are the series elastic and parallel elastic components of the Hill model built into the myofibrillary structure, or do they represent the connections between myofibrils and other components of the film?" Dr. Mommaerts, would you care to answer? Mommaerts: Originally, I am sure, in many experimental situations the series components probably were representing properties of the string to which the muscle was tied, other connections, and various other aspects of the recording instruments. But as we learned to eliminate those, the series elastic components became less and less evident; nevertheless, there does seem to remain something left. Let me mention one or two possibilities of what it might be. One possible localization for the contractile component is in the region where actin and myosin filaments overlap and interact, i.e., at the seat of the movement. Or, the series elastic components could be the parts of the thin actin filament that are not overlapping the myosin filaments. Between these two main choices one could make a distinction by studying the length-tension diagrams of the series elastic components as a function of overlap or of the exposed lengths of the thin filaments. We started such experiments, but the issue is not yet settled. Hall: Many of us have doubtlessly been wondering how much of what has just been said is applicable to the assessment of patients whose thoraces may not be open for the purpose of diagnostic testing. Would those of you who are more clinically inclined care to comment on this? What can you say about the practical application of these concepts? May I ask Dr. Langer to address himself to this? Langer: As indicated by both Drs. Mitchell and Sonnenblick, there is probably still some argument about what is the best parameter to employ for the definition of contractility, but I think the general consensus tends to favor the rate of force development. This becomes extremely difficult to evaluate in the intact heart, mainly because of the various parameters involved. Some of these are fairly directly measured, as has been indicated in the discussion. The one that is probably the most difficult to measure and control is that time during the course of the active state which one selects to make a measurement in the control and in the possibly abnormal state. Of necessity, this time parameter will vary with reference to the conventional standards for timing cardiac events because of differences in duration of the isovolumic state which arise in a ventricle that has to develop increased wall tension in a dilated state. I think that a very rigid evaluation of time parameters in the course of a single cycle is most difficult to achieve. Sonnenblick: I do not feel quite as pessimistic, although there are still some matters of controversy.

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183

I think that we have identified what we need to know; as Dr. Brady pointed out, we need measurements of force, velocity and length, fitting within a framework of time. We can make these measurements using various techniques, such as angiography for volumes and fiber lengths, but we need to be able to measure flow, which has to do with fiber shortening rates. With the use of various angiocardiographic techniques, volume can be measured. Thus, one can come up with relationships between tension and velocity of shortening, and in this manner separate patients with myocardial disease from normals. There has been some experience along these lines at the National Heart Institute which shows that they are readily separable conditions. This is especially true when dealing with situations where the heart is abnormally loaded, such as in aortic insufficiency in which there are very large changes in the afterload. These clinically useful handles on the measurement of force, velocity, length and time undoubtedly will improve as our methods of angiography improve. Hall: In summary, then, if you can measure the diastolic volume, the rate of change in volume during the cycle, and the rate of change of pressure, you have the necessary data to make an approximation of the force-velocity relationship. Is that true? Langer: Yes. Brady: I may mention, on the pessimistic side again, that one of the real problems is knowing what is the actual load on the fiber. In the whole heart it is very difficult to know what the distribution of forces between fibers really is. Yet their accurate measurement is necessary if we are to characterize heart performance in terms of basic phenomena. There are some good ideas being developed in approaching this, so I think these efforts are bound to lead to better results in the near future. REFERENCES and POOL, P . E . , Association of depressed myofibrillar adenosine triphosphatase and reduced contractility in experimental heart failure. Circ. Res., 1967, 21: 717-725.

1. CHANDLER, B . M . , SONNENBLICK, E . H . , SPANN, J . F . ,

2 . LESCH, M . , PARMLEY, W .

W . , HAMOSH, M . , KAUFMAN, S., a n d SONNENBLICK,

E. H., Effects of acute hypertrophy on the contractile properties of skeletal muscle. Am. }. Physiol, 1968, 214: 685-690. 3 . SPANN, J . F . , JR., BUCCINO, R . A . , SONNENBLICK, E . H . , a n d BRAUNWALD,

E.,

Contractile state of cardiac muscle obtained from cats with experimentally produced ventricular hypertrophy and heart failure. Circ. Res., 1967, 21: 341-354.

PROBLEMS IN THE MEASUREMENT OF VENTRICULAR VOLUMES H. J. C. SWAN Department of Cardiology Cedars-Sinai Medical Center Los Angeles, California

In spite of major efforts, the accuracy of determination of ventricular volumes remains unclear and much information in the literature is contradictory (7). The purpose of this paper is to summarize the current state of ventricular volume measurements as applicable to the relatively intact organism, including man. Ideally, intraventricular volume would be recorded in a quantitative and continuous manner utilizing methods which would interfere minimally or not at all with physiological function and which would be minimally traumatic or completely atraumatic in their application. At the present time such methods are not available. The majority of attempts to obtain absolute measurements of ventricular volumes have utilized two fundamentally different principles, the angiographic method, and the indicator dilution method. The angiographic method is based on the presentation of a geometric image of the ventricular chamber utilizing the contrast-filled ventricle with definition of specific dimensions by radiological techniques; this procedure does permit a semicontinuous (6/sec. with film change, 30-80/sec. with cinetechniques) estimation of ventricular volumes throughout a single cardiac cycle or several cardiac cycles; it is, however, associated with injection of a physiologically active substance into the vascular bed, and its application is limited by the complexity of equipment required as well as by the quantity of contrast material that can be administered safely to an individual or experimental animal. The dilution method requires the placement of a catheter into the left ventricle and a sensor in the aorta, but does not need the injection of substantial quantities of substances with a significant cardiovascular action, so that it may be repeated many times; applications of this method permit the estimation of only maximal and minimal chamber volume, and do not allow the definition of the time-course of such changes. The Angiographic Method The earlier direct volume measurements of Arvidsson ( 2 ) , Dodge and associates ( 9 ) , and Miller & Swan (20) were based on angiocardiography em185

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HEART

DISEASE

ploying a semicontinuous filming technique with a six- or twelve-per-second biplane roll-film changer. The single plane cineangiographic technique has been applied both in Scandinavia by Gribbe (12) and in the United States by Chapman ( 6 ) and by Hallerman (13). Newer applications of this technique include biplane cineangiography, with automatic reduction of the data so derived. The measurement of volumes by angiography depends upon certain geometric assumptions. The specific refinements applied to analysis of angiograms to improve correlations by empiric equations ( 8 ) may be of less importance than the general assumption that the cardiac ventricles are adequately represented angiographically by an ellipsoid or by a solid of similar shape which is still appropriate at all times in the cardiac cycle. Most errors in such assumptions relative to the measurement of volumes from angiographic representation tend toward overestimation in the final computation, while a few tend to underestimate the true volume. The dimensions used for the calculations of left atrial and left ventricular volumes from biplane angiograms by the method of Arvidsson are shown in Figure 95, the sequence of filming in Figure 96, and the resulting data in Figure 97. Figure 97 also shows (left panel) left ventricular pressure (center ), left atrial volume (VLA) and left ventricular volume ( VT.V ). When these are combined, a relatively smooth curve of the change in ventricular volume is depicted (right panel). From this both the maximum (or end-diastolic) and the minimum (or end-systolic) volumes can be readily calculated, and the rate of change of volume as well as the relation of volume change to pressure change can also be determined. Table 12 shows some of the simple values that can be calculated when absolute end-systolic and end-diastolic volumes are known. The difference between the end-diastolic and end-systolic volumes is equal to the total volume load, including any blood regurgitated at either mitral or aortic valves. The ejection fraction (EDV-ESV) /EDV is the proportion of total ventricular content expelled during systole; it remains relatively constant in normal subjects and in patients with cardiac malformations but without heart failure. Stroke work generated per unit end-diastolic volume may also be calculated; this is a crude index of the Frank-Starling relationship. Total ventricular stroke work or stroke work index can be calculated as well, even in the presence of valvular regurgitation. If an estimate of the forward stroke volume can be obtained by an independent method, then the absolute volume of regurgitation can be calculated. Figure 98 shows unpublished data collected by Dr. Graham Miller working in my laboratory at the Mayo Clinic. The independent estimate of the magnitude of insufficiency was supplied by cardiovascular surgeons of great experience and reliability; this allows the magnitude of regurgitation to be defined with some qualitative degree of accuracy. If the normal stroke volume is approximately 45 ml/m2 then moderate regurgitation represents a

MEASUREMENT

OF V E N T R I C U L A R

VOLUMES

187

Figure 95. Biplane angiographic measurement of ventricular volume. Above: AP and lateral angiocardiogram showing left ventricle, left atrium (dotted outlines) and aorta following injection of contrast material into the pulmonary artery; the cardiac chambers are in end-diastole. Below: Dimensions used for the calculation.

backflow of one to two times the stroke volume. Clinically severe regurgitation is present when three to five times the forward stroke volume refluxes. However, an independent method of comparison is not yet available for use in man, although backflow at the level of the aortic valve has been measured by appropriate flowmeter devices in the experimental animal (1). Certain simple questions in regard to the angiographic method of volume estimation can now be considered. First, is it possible accurately to measure volumes of the general shape of the heart from an angiographic image? Bunnell and coworkers (5), working in Nordenstrom's laboratory in Stockholm in 1959, measured the volumes of casts made with Wood's metal in situ in the dog thorax. The data showed an extremely small intra-individual variability when the films were analyzed by several observers using the methods of Arvidsson (2), and the deviation

188

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DISEASE

Figure 96. Electrocardiogram and femoral artery pressure during angiography for ventricular volume measurement. Contrast was injected at a uniform rate, as indicated by the linear movement of the injection syringe marker. Biplane exposure of X-ray film occurred as indicated. The concentration of contrast was adequate for delineation of ventricular chamber size from exposure No. 9 through No. 22.

from true volumetric (water displacement) measurements was approximately 5 per cent. Similar data have been found post mortem for the human heart by Dodge and associates (9) and by Davila & Sanmarco (8). Hallerman et al. (13) took a series of animals killed for other purposes and obtained both very large hearts, corresponding in volume to end-diastolic, and some small hearts in rigor mortis in which the volumes were end-systolic (Table 13). In comparison with displacement volumes there was no significant difference in seven large casts, but for three small casts in the contracted state, the X-ray estimate was low by approximately 10 per cent. The total evidence indicates that it is possible to measure by X-ray photography with reasonable accuracy the volume of objects of the general shape and size of the ventricular content. Can the angiographic method measure change in volumes with reasonable accuracy? Figure 99 demonstrates the relation of stroke volume determinations by indicator dilution plotted against the difference between endsystolic and end-diastolic volumes in a series of human subjects of widely

MEASUREMENT

OF

VENTRICULAR

SEQUENCE

-RAY

EXPOSURES

VOLUMES

189

COMPOSITE

16 fir

SECONDS

stantì

AFTER

R

WAVE

Figure 97. Left: Volume measurements obtained in sequence following injection of contrast; ventricular volumes (white circles) and atrial volumes (black circles) are related to the recorded intraventricular pressure. Right: Values for ventricular volumes, plotted in time after the R-wave of the electrocardiogram; note that the least ( E S V ) and greatest ( E D V ) volumes can be readily determined; a general approximation of the time-course of volume change is also evident.

differing body size but without valvular incompetence. The correlation between the methods is high, but the angiographic method indicates a larger stroke volume than the indicator dilution method. However, if an error in the measurement of end-diastolic ( E D V ) or end-systolic ( E S V ) volume exists, it is systematic and approximately equal. T A B L E VALUES

DESCRIPTIVE

OF

12

CARDIOVASCULAR

ON V O L U M E

FUNCTION

DEPENDENT

MEASUREMENTS

Title

Symbol

Normal

End-diastolic volume End-systolic volume Stroke volume Ejection fraction Stroke work (SW) Function index Effective stroke volume Regurgitant volume (VR) Regurgitant fraction

VED

70-85

VES

23-29

(VED-VES)

44-53

(VED — VES) /VED

0.67-0.74

(VED - VES)

XPS

70

SW/VED

1 .0

VS

44-53

(VED - VES) -

VS

VR/(VED — VES)

0 0

Unit ml/m2 ml /m2 ml/m2 dimensionless g-m /m2 g-m/m 2 ml/m2 ml/m2 dimensionless

190

CONGENITAL

HEART

DISEASE

200

I BO

•

=

PREDOMINANT

MITRAL

INSUFFICIENCY

m

-- PREDOMINANT

MITRAL

STENOSIS

A

•

AORTIC

PREDOMINANT

INSUFFICIENCY

160

140

«o

120

-V ES ) and stroke volume determined by the indicator dilution technique ( V S ) in patients without valvular incompetence.

equaled the volume of blood injected. In confirming these observations, Sanmarco and coworkers (24) demonstrated also that absolute end-systolic and end-diastolic volumes increased by 5 to 15 per cent immediately following injection of contrast material. In summary, it may be stated that volume determinations by angiography are sufficiently accurate for clinical practice. They permit demonstration of major differences between normal subjects and patients with heart disease. They permit quantitative measures of stroke work, ejection fraction, and regurgitation. They allow assessment of myocardial as opposed to mechanical factors in valvular heart disease, and probably also in disease states involving the pericardium, endocardium and myocardium. The Indicator Dilution Method The principles developed by Bing and associates ( 4 ) underlie all such applications to the estimation of volumes by the dilution technique. The assumptions fundamental to its practical use, outlined by Holt (15), should not be significantly affected by the indicator used, whether conductivity, thermal, dye indicator, or radioisotope. Figure 100 shows a typical aortic clearance curve, obtained following injection of cardiogreen into the left ventricle with a catheter-densitometer system of high dynamic response (25). This figure demonstrates that indica-

192

CONGENITAL ( Dog

HEART -

18

DISEASE

kg.) (mg./L.)

SAMPLING

RATE

-

135 ml /minute

Figure 100. Determination of left ventricular volume from aortic root dilution curves following injection of cardiogreen into the left ventricle as shown in the center panel. The experimental preparation is characterized by the X ray on the left. Note the clearly defined concentration peaks from which the data indicated to the right of the panel are derived. The heart rate was 135 beats/min., and the values for end-systolic and enddiastolic volumes were calculated as indicated.

tor dilution curves obtained under experimental conditions and at relatively high heart rates can give an identifiable concentration plateau for successive beats, and therefore permit the determination of an appropriate K value with calculations of systolic and diastolic volume as shown. Such curves are in no way inferior to those which have been obtained by other methods, although the superiority of the fiberoptic method (17), which does not necessitate blood withdrawal, is clearly evident in applications to man. The dilution method, originally described by and used by Holt (15) and others (11, 13, 22, 25) has consistently produced values for left ventricular endsystolic volume which seemed to be large in relation to the stroke volume. In all of these studies the end-systolic volume exceeded one-half of the enddiastolic volume. Table 14 shows data obtained by Hallerman et al. (13) in a direct comparison of volumes by dye dilution and cineangiographic methods for determination of the volume of the canine left ventricle. The angiographic method tended to overestimate stroke volume slightly when compared with the indicator dilution method, the accuracy of which has already been established in the measurement of volume flow. However, the end-diastolic and end-systolic volumes as measured by the angiographic technique were a

MEASUREMENT

OF

VENTRICULAR

VOLUMES

193

T A B L E 14 COMPARISON

OF L E F T

VENTRICULAR VOLUMES BY D Y E

DILUTION

AND

ANGIOGRAPHY*

(Average Values—7 Dogs) Volume

Dye ml/10 kg

Angiography ml/10 kg

Stroke End-diastolic End-systolic

9.6 34.8 24.8

11.4 18.3 6.9

Ratio Dye/Angiography 0.84 1.90 3.60

* Data from Hallerman, Kastelli & Swan (13).

fraction of those measured by the indicator dye dilution technique. T h e end-systolic volume by dye dilution expressed as a fraction of the volume by angiography also showed a wide variation, from 1.9 to 9.3. T h e stroke volume expressed as a ratio of end-diastolic volume showed values of 2 5 per cent by the dye and 62 per cent by the angiographic methods. T h e literature on this topic is in general agreement with these data ( 3 ) . Among the factors that require consideration is the influence of sampling location and injection site. Figure 101 shows the variation in the contour of dilution curves obtained simultaneously at two positions, one just above the ( Dog - 24 kg. ) AORTA (2 cm. Distal

to

Valve)

AORTA (At

Valve)

FEMORAL ARTERY EC G Figure 1 0 1 . Variability in dye dilution curves obtained simultaneously at two differing positions in the ascending aorta following sudden injection into left ventricle. ( F . J. Hallerman, G. C. Rastelli and H. J. C. Swan, unpublished observations.)

194

CONGENITAL

HEART

DISEASE

aortic valve, and one 2 cm distal to the aortic valve. The dilution curve recorded in the aorta is a time- and not a volume-averaged curve. The wide variation in the area under a given dilution curve is reflected in the cardiac output determinations shown in Figure 102. Each point in this figure represents approximately ten determinations without alteration in the position of the sampling catheter in the aortic root. Note first the small to moderate variation about the individual mean provided by each method and, second, the wide random variation about the line of identity. Clearly, the quantity of dye recognized by such a sampling system in the aortic root is highly dependent upon the position of the detecting catheter. The phenomenon of incomplete mixing of blood entering the canine left ventricle with the residual volume has been extensively studied (18, 25), and is reflected in the changing concentration during each cardiac cycle, as shown in Figure 101. Its occurrence in the canine heart is now generally accepted. Although theoretical considerations suggest that this phenomenon and that of nonrepresentative sampling in the aortic root referred to above need not negate the assumptions basic to the dilution method, it is unfortunate that, with one exception (23), no serious attempts have been made to

1000

CARDIAC

OUTPUT

(Aortic

4000

3000

2000

1000

Root

Sampling

Site

— ml. /

min.)

Figure 102. Comparison of cardiac output values determined from simultaneous dilution curves obtained in the aorta and at the femoral artery. The mean values are indicated by the points. (F. J. Hallerman, G. C. Rastelli and H. J. C. Swan, unpublished observations.)

MEASUREMENT

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VOLUMES

195

Figure 103. Experimental preparation for the determination of aortic washout characteristics. This X-ray projection demonstrates catheters placed in the left ventricle for injection of indicator or contrast, in the right ventricle for electrical establishment of heart rate, in the aortic root for injection of thermo indicator, and in the central aorta (basket catheter) with an aortic thermistor for the recording of temperature changes. For purposes of demonstration, a small quantity of contrast has been injected into the aorta to provide an outline of the aorta and its major branches. The serrated elements to the right of the X ray indicates 1 cm distances at mid-heart position.

establish error levels in vivo by those who derive data by its application. As shown in Figure 102, a wide variability between animals can coexist with a small variability within a given experiment. Recently, a third phenomenon which may be of more importance than that of ventricular or aortic nonmixing has been recognized. Freis & Heath (10) observed the effects of injection of an indicator into the aortic root with sampling of its concentration above the aortic valve. Several beats were required to clear the indicator from the ascending aorta. This means that the content is not pushed forward in a bolus, but is cleared by mixing of the blood ejected from the left ventricle with that which was present in the aortic root, with propulsion of part of this mixture distally. Swan, Knopp & David (26)

196

CONGENITAL

HEART

DISEASE

studied this phenomenon in greater detail in the dog (Figure 103). One catheter was placed in the right ventricle for electrical stimulation of the heart, and a second in the left ventricle for injection of indicator dye. A detecting catheter was positioned centrally in the ascending aorta by means of a basket device in which an aortic thermistor was mounted, and a catheter for indicator injection was placed in the aortic root. Other catheters were utilized for sampling in the aortic root or in the outflow tract of the left ventricle and in the ascending aorta. Thermal dilution curves quite similar to those of Freis & Heath (10) were obtained (Figure 104). The step function characterizing the disappearance of thermal indicator demonstrated in this animal were typical of virtually all dilution curves obtained from the aortic root. In fact, no animal cleared the thermal indicator from the aorta in one beat. The clearance of indicator can in general be described by the relation (Tn — To)/ (T„-i — To), where T„ and Tn-i are observed temperature values, and T0 is the original blood temperature. Many factors alter this ratio. Prominent among these are heart rate and stroke volume, as shown in Figure 105. Stroke volume appears to be the basic mechanism, as demonstrated in an experiment in which the heart was paced at constant rate and (Dog -21 kg.)

Figure 104. Changes in temperature following injection of cold saline into the aortic root. Note the clearance is a stepwise function occurring over at least 6 beats. This tracing represents one of the most rapid clearances of "heat" seen in this series of experiments.

MEASUREMENT CARDIAC OUTPUT (L./minute)

3

OF

VENTRICULAR Dog 8

\

-J

2

L_

I

197 Dog:

M_

5 O

7 A e •

0.7 o A

.

35

STROKE

VOLUMES

0.6

VOLUME

MEAN

(ml.)

15

_l

I

I

L

Cn Cn-I 0.5

0.6

MEAN Cn Cn-I

0.4

0.5

70

-J

I

90

l

HEART RATE ( beats /minute1

L

110

20 STROKE

40 VOLUME

(mi)

Figure 105. Effect of heart rate and stroke volume on the aortic clearance rate. Left: Experimental data obtained on one dog; the heart rate was increased from 7 2 to 120/min. by electrical pacing; cardiac output remained unchanged and stroke volume fell; the mean ratio (Tn—T0)/(Tn., — T0) is here represented as Cn/Cn_, (the ratio of successive changes in temperature per heart b e a t ) . Right: Relationship between stroke volume and C,JCn_, in 3 animals of approximately equal size; the inverse relationship is striking.

stroke volume was reduced by inflation of a balloon in the inferior vena cava. For a heart rate of 110 beats/min. this resulted in an increase in the ratio (Tn — T„)/(Tn-i -- T„) from 0.54 at 30 ml stroke volume to 0.71 at 8 ml stroke volume. Reduction in stroke volume will automatically cause a larger concentration fraction in the aortic root because a smaller volume is ejected from the left ventricle to mix with the relatively constant central aortic volume. A preliminary indication of the significance of the "aortic mixing volume" in regard to determination of ventricular volume is shown in Figure 106. At the first arrow, thermal indicator is injected into the left ventricle and the concentration ratios are measured in the outflow tract of the left ventricle and in the aortic root. If the theory of transfer of concentrations without distortion into the aorta pertained, then the two values should be similar. As can be seen, the outflow tract had, in fact, a concentration ratio of 0.57 and a simultaneously recorded aortic concentration (displaced in time by one cardiac cycle) was 0.67. At the second vertical arrow, thermal indicator was injected into the aortic root and the clearance of the aorta was described by the concentration ratio 0.55. The heart rate was 100 beats/min. Clearly, the relation of stroke volume to residual aortic root volume, and to end-systolic ventricular volume, may be of a similar order of magnitude. Holt (16) has questioned the conclusion that such evidence as presented herein means that the aorta acts as a significant secondary mixing chamber in regard to blood ejected from the ventricle, while Rapaport (21) claims that, even if secondary mixing occurs, the aortic chamber is of no conse-

198

CONGENITAL

HEART

DISEASE

(Dog - 18 kg.)

Figure 106. Ventricular and aortic clearance of an indicator; continuous recording. Left: Thermal dilution curves recorded following injection of cold saline (first arrow) into the left ventricle with subsequent changes in the outflow tract of the left ventricle and in the central ascending aorta; note that the ratios of successive ( T „ — T 0 ) / { T n _ , — T0) values (here represented as Cn/Cn.,) are less in the ascending aorta. Right: An injection of cold saline has been made into the aortic root (second arrow); not that (Tn — T0/(Tn_,— T0) is approximately equal to that obtained in the outflow tract of the left ventricle and that no temperature change is seen retrograde from the aortic root into the outflow tract of the left ventricle.

quence since it is smaller than the ventricular volume. Nevertheless, the presence of nonmixing, anomalous sampling, and secondary chamber effects are now clearly recognized, and their magnitude may vary greatly with physiological adjustments as well as with the technical procedures related to injection and sampling. It would appear that the definition of the magnitudes of the component errors is incumbent on those who claim that the dilution method as presently applied provides correct values for ventricular volumes and for the ejection fraction. Thus far, this has been incomplete. In one of few such attempts ( 1 8 ) , a comparison was made between dilution volumes and actual post-mortem (five minutes) volume measurements at a high distending pressure in three dogs. The greatest variation was 4 ml. However, the technique used permitted displacement of the ventricular septum, which has been shown ( 1 9 ) to produce volume estimates greatly in excess of those which are obtained when pressures are maintained in the contralateral ventricle. As stated earlier, an acceptable absolute reference model of left ventricular volume is difficult to achieve. However, the errors associated with angio-

M E A S U R E M E N T

OF

V E N T R I C U L A R

VOLUMES

199

graphic technique should tend towards measured values of greater magnitude than the true values. Nevertheless, all angiographic values for the ventricular volume at end-systole and end-diastole are substantially less than those obtained thus far by the indicator dilution technique. In many instances the dynamic response characteristics of the sampling system are undefined and probably inadequate—particularly at high heart rates. At present, therefore, it appears that the angiographic method provides the most reliable means for measuring ventricular volumes in the physiological state and should be used as the reference standard. The error in such values is in the range of ± 20 per cent. In its applicability, however, this method is far from ideal, particularly in man, and the establishment of criteria or conditions under which values by the indicator method are accurate or the development of new techniques for determination of ventricular volume in the intact animal and man is still an open and profitable field of research endeavor. REFERENCES 1. ARMELIN, E . ,

2. 3.

4.

5.

6. 7. 8.

MICHAELS, L . , MARSHALL, H . W . ,

DONALD, D . E . ,

CHEESMAN,

R. J., and WOOD, E. H., Detection and measurement of experimentally produced aortic regurgitation by means of indicator-dilution curves recorded from the left ventricle. Circ. Res., 1963,12: 269-290. ARVIDSSON, H . , Angiocardiographic determination of left ventricular volume. Acta Radiol. Diagn. (Stockholm), 1961, 56: 321-339. BARTLE, S. H., and SANMARCO, M. E., Comparison of angiocardiographic and thermal washout techniques for left ventricular volume measurement. Am. J. Cardiol, 1966, 18: 235-252. BING, R . J., HEIMBECKER, R . , and FALHOLT, W . , An estimation of the residual volume of blood in the right ventricle of normal and diseased human hearts in vivo. Am. Heart J., 1951,42: 483-502. BUNNELL, I. L . , IKKOS, D . , RUDHE, U . G . , and SWAN, H . J . C . , Left-heart volumes in coarctation of the aorta. Am. Heart J., 1961, 61: 165-172. CHAPMAN, C . B . , BAKER, O . , REYNOLDS, J . , and BONTE, F . J . , Use of biplane cinefluorography for the measurement of ventricular volume. Circulation, 1958,18: 1105-1117. DAVILA, J. C., (Ed.), Symposium on measurement of left ventricular volume. Am. }. Cardiol, 1966, 18: 1-42; 208-252; 566-593. DAVILA, J. C., and SANMARCO, M. E., An analysis of the fit of mathematical models applicable to the measurement of left ventricular volume. Am. J. Cardiol, 1966, 18 : 31-42.

9 . DODGE, H . T . , SANDLER, H . , B A L L E W , D . W . , a n d LORD, J . D . , JR., T h e u s e o f

biplane angiocardiography for the measurement of left ventricular volume in man. Am. Heart J., 1960, 60: 762-776. 1 0 . FREIS, E . D . , and HEATH, W . C . , Hydrodynamics of aortic blood flow. Circ. Res., 1964, 14: 105-116. 11. GORLIN, R . , ROLETT, E. L., YURCHAK, P. M., and ELLIOTT, W. C., Left ventricu-

200

12.

13.

14 . 15.

16.

CONGENITAL

HEART

DISEASE

lar volume in man measured by thermodilution. J. Clin. Invest., 1964, 43: 1203-1221. GRIBBE, P., HIRVONEN, L., LIND, J., and W E G E L I U S , C., Cineangiocardiographic recordings of the cyclic changes in volume of the left ventricle. Cardiologia, 1959, 34 : 348-366. H A L L E R M A N , F. J., RASTELLI, G. C., and SWAN, H. J. C., Comparison of left ventricular volumes by dye dilution and angiographic methods in the dog. Am. J. Physiol., 1963, 204: 446-450. , Effects of rapid injection of heparinized blood into right and left ventricles in dogs. Radiology, 1964,83: 647-655. H O L T , J. P., Estimation of the residual volume of the ventricle of the dog's heart by two indicator dilution technics. Circ. Res., 1956, 4: 187-195. , Indicator-dilution methods: indicators, injection, sampling and mixing problems in measurement of ventricular volume. Am. J. Cardiol., 1966, 18 : 208-225.

1 7 . HUGENHOLTZ, P . G . , G A M B L E , W . J . , MONROE, R . G . , a n d POLANYI, M . , T h e u s e

18.

19. 20. 21. 22.

23.

24.

25.

26.

of fiberoptics in clinical cardiac catheterization. II. In vivo dye-dilution curves. Circulation, 1965, 31: 344-355. IRISAWA, H., W I L S O N , M. F., and RUSHMER, R. F., Left ventricle as a mixing chamber. Circ. Res., 1960, 8: 183-187. LAKS, M. M., GARNER, D„ and S W A N , H. J. C., Volumes and compliances measured simultaneously in the right and left ventricles of the dog. Circ. Res., 1967, 20: 565-569. M I L L E R , G. A. H., and S W A N , H. J. C., Effect of chronic pressure and volume overload on left heart volumes in subjects with congenital heart disease. Circulation, 1964, 30 : 205-216. RAPAPORT, E., Usefulness and limitations of thermal washout techniques in ventricular volume measurements. Am. J. Cardiol., 1966, 18: 226-234. RAPAPORT, E., WIEGAND, B. D., and BRISTOW, J. D., Estimation of left ventricular residual volume in the dog by a thermodilution method. Circ. Res., 1962, 11: 803-810. R O L E T T , E . L., SHERMAN, H., and GORLIN, R., Measurement of left ventricular volume by thermodilution: an appraisal of technical errors. J. Appl. Physiol., 1964, 19: 1164-1174. SANMARCO, M. E., FRONEK, K., PHILIPS, C. M., and DAVILA, J. C., Continuous measurement of left ventricular volume in the dog. II. Comparison of washout and radiographic techniques with the external dimension method. Am. J. Cardiol, 1966, 18: 584-593. S W A N , H. J. C., and BECK, W., Ventricular nonmixing as a source of error in the estimation of ventricular volume by the indicator-dilution technic. Circ. Res., 1960, 8: 989-998. SWAN, H. J. C., KNOPP. T. J., and DAVID, P. R., Effect of aortic mixing on determination of ventricular volumes by washout. Physiologist, 1965, 8: 284.

ASSESSMENT OF MYOCARDIAL FUNCTION IN CONGENITAL HEART DISEASE 0

PAUL G. HUGENHOLTZf and HENRY R. WAGNER Children's Hospital Medical

Center

and D e p a r t m e n t of Pediatrics, Harvard M e d i c a l Boston,

School

Massachusetts

T h e search for a better understanding and definition of cardiac function continues. More specific and earlier recognition of malfunction is mandatory if surgical correction of congenital cardiac lesions is to be more successful than it has been to date. T h e following is a review of the results of two techniques that have been applied to the assessment of left ventricular function as affected by a variety of congenital cardiac defects. All data were obtained as part of diagnostic cardiac catheterization of the left and/or right side of the heart. T h e techniques under discussion are quantitative biplane angiocardiography and an indicator dilution technique employing the fiberoptic hemoreflection system with indocyanine green as the indicator. T h e specific parameters analyzed were the end-diastolic volume ( E D V ) , ejected fraction ( E j F ) , and the forward stroke volume ( S V ) under resting conditions in various lesions with either a dominant pressure or volume load. In addition, the thickness of the ventricular wall and the left ventricular muscle mass was estimated. Finally, the relationship of the left ventricular muscle mass to the predominant load, whether this consisted of excess pressure or of augmented volume, will be discussed, particularly in terms of ventricular wall tension, stress, and strain. In specific instances, the relationship of stress and strain will be described, emphasizing the significance of Young's modulus in an effort to estimate the forces acting upon the ventricular wall. This work was done during P.G.H.'s tenure of an Established Investigatorship of the American Heart Association, and was supported in part by Program Project Grant H E 1 0 4 3 6 - 0 1 , National Heart Institute of the National Institutes of Health, Traineeship Grant HE-5310-08. T h e authors wish to express their appreciation to Mrs. Elizabeth Hull and Miss Elizabeth Nilsson for their technical assistance and secretarial efforts, f Present affiliation: Department of Cardiology, University Hospital, University of Rotterdam, The Netherlands. 0

201

202

CONGENITAL

HEART

DISEASE

METHODS AND MATERIALS

The records of 75 patients in whom fiberoptic ( F O ) dye dilution curves were obtained during catheterization of the left side of the heart were reviewed. Data regarding SV, E j F , E D V , and end-systolic volume ( E S V ) were tabulated. Records were available for 123 patients in whom biplane angiocardiograms with injection of the contrast medium into the left ventricle had been performed. From these, data were extracted regarding SV, E j F , E D V , and ESV, as well as left ventricular wall thickness and muscle weight ( L V W ) . In five additional patients only the latter two measurements were available. In 15 patients representative for specific lesions, a detailed analysis was made of left ventricular wall tension, stress, and strain following the principles and definitions outlined by Sandler & Dodge ( 1 0 ) . In the F O group there were 17 patients with valvular aortic stenosis ( A S ) , 11 with aortic regurgitation ( A R ) , 9 with muscular subvalvar aortic stenosis ( I H S S ) , 9 with atrial septal defect ( A S D ) secundum type, 7 with ventricular septal defect ( V S D ) , 7 with a variety of lesions affecting the left ventricular muscle ( M Y O C ) , 7 with mitral regurgitation ( M R ) , and 3 with mitral stenosis ( M S ) . Five patients with lesions affecting the right ventricle, pulmonic stenosis ( P S ) , were selected as controls. In the group studied angiocardiographically, these numbers were respectively, 32 with AS, 15 with AR, 13 with IHSS, 21 with VSD, 14 with MR, 7 with myocarditis, and 11 who served as controls since no left ventricular disease could be demonstrated. There were also 6 patients with coarctation and 4 with MS. The ages ranged from 6 weeks to 58 years, with more than 80 per cent of the patients younger than 18 years. There were 52 females and 76 males. Details regarding the fiberoptic indicator dilution method, such as calibration procedure, and the degree of correspondence of SV between FO, Fick, and angiocardiographic methods in nonregurgitant lesions have been given elsewhere (5, 11) and will not be repeated here. The angiocardiographic method, based on the method of Dodge and Sandler (2) for volume measurements and on the technique described by Rackley and coworkers ( 9 ) for muscle mass, has been modified and simplified slightly, as summarized below. Biplane angiocardiograms were recorded at 6 or 12 frames per second over an average of 2.5 seconds. Selection of the faster filming speed depended on the patient's size. A signal marking exposure time, recorded simultaneously with the electrocardiogram ( E C G ) , permitted the exact timing of the films (Figure 107). Intraventricular pressure was recorded immediately preceding, often during, and always following the angiocardiograms. Pressures were measured with a Statham P23Db strain gauge and a 100 cm No. 8 F sidehole catheter. Only in small children and infants were thinner catheters used. Renovist, 2 ml/kg (maximum dose, 100 ml), was injected in all cases.

MYOCARDIAL

FUNCTION

,1.,, lMIIMriuillllJlil.llilllll.il.I. illllilUllllll.

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ASSESSMENT

203

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Figure 221. Demonstration by roentgen videodensitometry of diastolic reflux across mitral valve after atrial contraction and relaxation during period of ventricular asystole in dog with acute heart block. Upper tracings: Slow-speed (2.5 cm/sec.) videodensograms showing changes in left ventricular density just downstream and in left atrial density just upstream from mitral valve; in both left and right panels, regular 2 : 1 atrioventricular driving was temporarily stopped immediately after injection of 4 ml of 69% Renovist; on cessation of driving, there was in right panel a period of total asystole, but in left panel a spontaneous atrial asystole (P) interrupted the period of asytole; both left ventricular densograms show marked reduction in X-ray transmission, commencing with injection of contrast medium; only atrial densogram on left shows marked downward deflection. Lower tracings: Fast-speed recording (15 cm/sec.) of same left atrial videodensogram as in left top panel, shown with simultaneous vascular pressures to indicate relation of left atrial density changes to vascular events during cardiac cycles (numbers 1, 2, and 3 in baseline) spanning period of injection of contrast medium; note that major deflection in left atrial videodensogram occurs after isolated atrial systole (A,); dashed line connecting lower and left upper tracings indicates identical instants in these simultaneous recordings; A' s , transmitted atrial systolic wave recorded in ventricle; A and V, atrial and ventricular electronic excitation artifacts.

428

CONGENITAL

HEART

DISEASE

the long diastole but is related specifically to atrial systole. The top panels show two sets of dilution curves recorded in the same dog (with heart block) in which the coupled atrial and ventricular pacing stimuli were suspended just at the completion of the injection, at which instant the maximal amount of the indicator was present in the left ventricle, and therefore the maximal sensitivity for detection of reflux into the atrium was attained. However, in the left upper panel, practically no indicator was detected for 1.5 seconds after completion of the injection; then a spontaneous atrial systole occurred (indicated by the P wave in the E C G ) and was followed immediately by a steplike increase in opacity of the left atrium, indicating the reflux of a considerable quantity of tagged blood back into the atrium. When a similar period of ventricular diastole occurred without the intervention of an atrial systole (right upper panel in Figure 221), practically no diastolic reflux was detected; only slight degrees of left atrial opacification occurred, and this was associated with the two ventricular contractions near and just after completion of the injection. The association of the diastolic reflux with atrial systole was illustrated more clearly when the same left atrial videodensogram (shown in the left upper panel of the figure) was rerecorded at a faster paper speed with the simultaneous vascular pressure pulses shown (lower panel). Immediately following the atrial-systolic pressure waves in the atrium (A s ) and the ventricle (A' s ), a sudden increase in left atrial opacity occurred, indicating that this atrial systole caused reflux of a considerable quantity of left ventricular blood back into the atrium—that is, diastolic atriogenic reflux. BIPLANE ROENTGEN VIDEOMETRY

Biplane roentgen videometry offers two important potential advantages for study of variations in volume and shape of the heart. One is that the recording of angiograms in the televised mode makes it possible to juxtapose and display the two projections of the left ventricle in the same video field, and thus to record these two projections side-by-side on the same video tape. Since the two projections are recorded simultaneously in the same video image, they are obviously synchronous with each other. It is also possible, as with roentgen videodensitometry, to record one or more physiologic variables, such as an ECG or a pressure pulse, on the same video tape. This greatly simplifies the tedious task of manually correlating and synchronizing the two separate pictures usually obtained from the two film changers or two cine cameras normally used for biplane angiography, and also simplifies the additional problem of synchronizing these pictures with the phases of the cardiac cycle. The second advantage is that, since the biplane images are in electronic form, they are readily amenable to electronic data processing and computing. If adequate electronic circuitry can be worked out to recognize the instants when the video scanning beam encounters the borders of the left ven-

VIDEOMETRIC

ANGIOGRAPHY

429

tricle, it will be possible to calculate, with the aid of computers, the shape and the volume of the left ventricle at the field repetition rate of the video system—60 times per second. Therefore, dynamic measurements of changes in left ventricular volume and shape under various hemodynamic conditions, including cardiac disease, are possible. Figures 222 and 223 illustrate the advantage of having physiologic recordings and biplane projections of the left ventricle on the same video tape to simplify the problems of measurement of end-diastolic and end-systolic ventricular volumes. Figure 222 is a recording of the left ventricular pressure and of the electrocardiogram superimposed on the recorded volume and duration of the injection of contrast medium. An electronic assembly was used to activate the shutter of a 35-mm camera, focused on the video screen, to obtain l/60th-second exposures at the end-diastolic and end-systolic phases of the first two cardiac cycles after completion of the injection of contrast medium, when maximal opacification of the ventricle is attained. Figure 223 illustrates the use of this technique by Dr. Tsakiris in our laboratory to study changes in left ventricular volume in dogs without thoracotomy during increased peripheral vascular resistance induced by infusion of angiotensin into the aorta and, in the same dog a few minutes later, during vasodilatation induced by infusion of acetylcholine ( 1 ) . The marked

Figure 222. Simultaneous recordings obtained during videoangiography and used to synchronize shutter of 35 mm oscillographic camera (bottom trace) to obtain pictures of left ventricle at end-diastolic ( E D ) and end-systolic (ES) phases of cardiac cycle. Movement of piston of injection syringe is recorded simultaneously on time-shared basis with electrocardiogram on auxiliary data track of same video tape as angiocardiogram. These two variables are also recorded in parallel, simultaneously with multiple other hemodynamic parameters, on conventional physiologic recorder. The dog's heart rate was maintained constant by electrical pacing of atria and ventricles via bipolar electrode catheters inserted percutaneously from left external jugular vein; respective shock artifacts produced in electrocardiogram by these stimuli are indicated by A and V. These ventricular stimuli were used to synchronize the camera shutter via an electronic variable delay and lockout assembly activated by movement of the syringe piston, so that the camera shutter was opened for 1 / 6 0 sec. and film advanced only during first one or two heart beats after injection of contrast medium, when maximal opacification of ventricle was attained. (From Williams, Sturm, Tsakiris & Wood, 5.)

430

CONGENITAL

Vasoconstriction

HEART

DISEASE

Vasodilatation

Figure 223. Biplane projections of left ventricle of 14.8 kg dog under morphine-pentobarbital anesthesia. Each pair of projections was recorded as a single video field, along with electrocardiogram on same video tape at rate of 60 fields/sec. A 35 mm camera focused on video screen and synchronized with the electrocardiogram was used to obtain these pictures of single fields associated with end-diastolic (ED) and end-systolic (ES) phases of cardiac cycle. Peripheral vasoconstriction and vasodilation were produced by intra-aortic infusion of angiotensin and acetylcholine, respectively. Note large differences in end-diastolic volumes (56 and 24 ml) and ejection fractions (30 and 75%) determined in same dog during these two circulatory states.

changes in end-diastolic volume and ejection fraction of the ventricle occurring in the same dog during these types of circulatory stress are evident. This application, while of value, exploits only a portion of the potential of this technique. The real challenge is to attempt to utilize the electronic signals which comprise the biplane video images for dynamic measurements of the dimensions of objects in the video image and for calculations of the changes in shape and volume of such objects. Figure 224 serves to introduce this problem. There is a sharp upward deflection of the oscillographic trace of the voltage fluctuations associated with the horizontal video line when the beam enters the image, just prior to encountering the margin of the rib cage. Then there is a downward plateaulike deflection when the beam crosses the opacified left oblique projection of the ventricle, an upward deflection as it crosses the radiolucent lung fields, and a second downward plateaulike deflection as it crosses the right anterior oblique projection of the ventricle. If it were possible to detect exactly when the video beam enters the left

VIDEOMETRIC

ANGIOGRAPHY Video

VIDEO

Line

0

IMAGE

240

OSCILLOGRAPHIC TRACE OF VIDEO LINE 130

Figure 224. Above: Biplane roentgen video images of right and left anterior oblique projections of left ventricle of 16 kg dog during first diastole after injection of 8 ml of 69% Renovist (90 kV; 1 mAmp.). Below: Video signal (in volts) from horizontal line 130, which traverses midportion of ventricular silhouettes; square wave deflections down to zero volts at ends of trace are synchronizing pulses which control horizontal travel of video beam and are associated with blanking of this beam during instants of its horizontal retrace; time interval between leading edges of these pulses is 63.5 ¡usee.; voltage of this signal is inversely proportional to roentgen opacity (expressed in optical density units) of portion of thorax being traversed by video beam; highest deflections occur when beam is traversing radiolucent lung areas; note two plateaulike downward deflections when beam traverses right and left oblique silhouettes of opacified left ventricle. (From Williams et al., 5.)

margin and leaves the right margin of the right oblique projection, and when it enters the right and leaves the left margin of the left oblique projection, and if the beam is sweeping at a known rate, a measurement of the diameters of a cross section of the ventricle in two planes at the site traversed by the horizontal line could be obtained. If this were done for each of the approximately 50 horizontal lines that traverse the ventricular silhouette, the area of each cross section calculated, and these areas summed, a value for the volume of the ventricle would be obtained. Furthermore, if the distances of the margins of the ventricle from the respective left edges

432

CONGENITAL

HEART

DISEASE

of the two video fields were measured, information concerning the shape of the ventricular cavity could be obtained for each vertical sweep of the video beam—that is, 60 times each second. Figure 225 illustrates this problem more fully. Three biplane projections of the heart are shown: a control picture without contrast medium, the end-diastolic phase of the first cardiac cycle after injection of contrast medium, and the subsequent end-systolic phase of this same heartbeat. In the oscillographic tracing of the video signal from one of the horizontal lines that traverse the left ventricle, the shorter period (indicating smaller diameter) required for the video beam to traverse the left ventricle during endsystole than during diastole is evident. The problem is to measure these distances accurately. This is complicated by the extraneous noise in the video signal and the large amount of extraneous information in the picture which hinders rather than assists the measurement of these diameters. Currently, techniques are being developed to preprocess the video signals to make it possible to recognize with reasonable accuracy the instants when, during its horizontal sweep, the video beam enters and leaves each margin of the ventricle.

Control

Diastole

Systole

Figure 225. Above: Biplane roentgen video images (anterior oblique projections) of left ventricle at end-diastole and end-systole used for determination of left ventricular volumes (8 ml of 69% Renovist into left ventricle; 90 kV, 1 mAmp.). Below: Video signals from horizontal line 130; widths of downward plateaulike deflections in middle thirds of center and right panels are proportional to diameters of ventricle at this cross section at end-diastole and end-systole, respectively. Special circuitry has been developed to measure these dimensions electronically for each of the approximately 50 horizontal lines traversing the ventricular silhouettes, and to input these data into a computer assembly for on-line calculation of the volume and shape of the ventricle 60 times per second. (From Williams et al., 5.)

VIDEOMETRIC

ANGIOGRAPHY

433

Figure 226. Biplane roentgen video image and associated oscillographic traces before and after preprocessing for videometric measurement of ventricular volume. For further details see text and legend of Figure 224.

The first stage in processing the signal is illustrated in Figure 226. The unprocessed video image and unprocessed oscillographic tracing are shown on the left. All of the video image except the two projections of the ventricle is masked out by an interactive manual-electronic technique, as illustrated on the right, so that only those portions of the signal which concern the ventricle directly remain. Then, a second technique is used to draw electronically a brightened line around each of the two silhouettes. By a manual and electrical shading technique, this line can be adjusted during continuous replay of single frames so that it finally coincides with the margins of and encompasses the whole ventricle both at end-systole and at end-diastole. This line encompasses all of the instants, indicated by numbers 1-4, when each of the horizontal video lines covering the biplane silhouettes enters or leaves the margin of the ventricle. This information will then be fed into a computer during replay of the video tape. The computer is programmed to compute the area of the cross sections of the ventricle corresponding to each horizontal line traversing the silhouettes and to sum these areas to obtain values for the ventricular volume 60 times each second. Progress in developing these techniques indicates that these objectives can be achieved. It is envisaged that, when success is attained, these methods will provide a very powerful tool for hemodynamic investigative diagnostic studies.

434

CONGENITAL

HEART

DISEASE

Discussion

Desilets: Dr. Wood, I would like to ask a question with regard to videodensitometry. Would your densitometer pick up contrast that you cannot see on the screen with your eye? Wood: Yes, it would. There are difficulties in quantitating this instrument. We have utilized it mostly for detection, which is possible by measuring differences in mean concentration times between different points in the circulation. There are still problems about obtaining quantitative data from the indicators. Osypka:9 One other advantage of the videodensitometer is that, if you have two videodensitometers, as we have, you can play two measurements simultaneously. That means you can detect the velocity of the dye or even make flow measurements. Question from the floor: What problems does nonmixing or incomplete mixing introduce? Wood: Some of the same problems you get with ordinary dilution techniques. Of course, you do have some advantages and some disadvantages. If you wish, you can cover the entire ventricular area with your sampling window. There is no question that, with this densitometer, very non-uniform mixing of the indicator can be demonstrated in the ventricle. REFERENCES A. G., VANDENBERG, R. A., DONALD, D . E., and W O O D , E. H., Changes in left ventricular end-diastolic volume-pressure relationship after acute cardiac denervation. Circulation, 1967, 36, Supp. 2: 253.

1. TSAKIRIS,

2 . W I L L I A M S , J . C . P . , O ' D O N O V A N , T . P . B . , CRONIN, L . , a n d W O O D , E . H . ,

In-

fluence of sequence of atrial and ventricular systoles on closure of mitral valve. J. Appl. Physiol., 1967, 22 : 786-792. 3 . W I L L I A M S , J . C . P . , O ' D O N O V A N , T . P . B . , STURM, R . E . , a n d W O O D , E .

H.,

Roentgen videodensitometric study of efficacy of mitral valve closure in dogs without thoracotomy. Physiologist, 1964, 7 : 287. 4 . W I L L I A M S , J . C . P . , O ' D O N O V A N , T . P . B . , VANDENBERG, R . A . , STURM, R . E . ,

and W O O D , E . H . , Atriogenic mitral valve reflux: diastolic mitral incompetence following isolated atrial systoles. Circ. Res., 1968, 22: 19-27. 5 . W I L L I A M S , J . C . P . , STURM, R . E . , TSAKIRIS, A . G . , and W O O D , E . H . , Biplane videoangiography. J. Appl. Physiol., 1968, 24: 724-727. 6. W O O D , E. H., STURM, R. E., and SANDERS, J. J., Data processing in cardiovascular physiology with particular reference to roentgen videodensitometry. Mayo Clin. Proc., 1964, 39: 849-865. ° Dr. Peter Osypka, Universitàts-Kinderklinik, Kiel, W e s t Germany.

NAME INDEX

A Abbott, M. E., 1 Adams, F. H„ 1-5, 37, 44, 131, 133, 295 Adler, S., 102 Antonopoulos, C. A., 18 Aristotle, 1 Arvidsson, H., 185, 187 Assali, N. S., 47-57, 75, 76, 101, 102, 113

B Bacon, R. L., 8 Baillie, 1 Barr, R. C„ 247-263, 347-368 Bauer, D. J., 92 Beck, R„ 75 Bell, J. W., 27 Bergofsky, E. H., 323 Bing, R. J., 191 Blalock, A., 2 Blanc, W. A., 131 Blinks, J. R„ 143 Blumenschein, S. D., 347-368 Boineau, J. P., 247-263, 347-368 Bostrom, H., 24 Bowditch, H. P., 135, 172 Brady, A., 135-138, 139-147, 181, 183 Braunwald, E., 101, 102, 124, 131, 132, 219, 226, 231-245, 265-271, 289-294, 305-307, 345 Bristow, J. D., 219 Brockman, S. K., 331, 332, 341-343 Brody, D. A., 373 Brown, J. W., 1 Bunnell, I. L., 187 Butler, J. K., 8 C Canent, R. V., Jr., 247-263 Capp, M. P., 247-263 Chapman, C. B., 186 Cloetta, M., 322 Collier, C. R., 373 Cook, C. D., 122 Cournand, A., 2 Crafoord, C., 2 Cross, K. W., 76

D David, P. R., 195 Davila, J. C., 188 Davis, C. L., 17 Dawes, G. S., 92

Day, W. C., 409-418 DeHaan, R. L., 7-15, 37, 43 Desilets, D. T., 434 Dodge, H. T., 185, 188, 202, 203, 205, 219, 228, 250, 267 Dollery, C. T., 321 Downing, S. E „ 59-100, 101, 103, 120, 124 Duffie, E. R„ Jr., 122 Durrer, D., 370

E Eisenmenger, 1 Emmanouilides, G. C., 131, 132 Erlanger, J., 331, 336 Evans, C. L., 229

F Fabricius, 1 Fallot, 1 Faraday, M., 383, 384 Flaherty, J. T„ 347-368 Forssmann, W., 2 Franck, O., 407 Frank, O., 59, 163, 164 Franklin, D. L„ 237-288, 305, 377-382, 407, 408 Freis, E. D., 195, 196 Frick, M. H., 295 Friedman, W. F., 37

G Gallie, T. M., 347-368 Gardner, R. M., 409-418 Gazetopoulos, N., 300 Gessner, I. H„ 17-26, 37, 43, 44, 101, 102 Gibbon, J. H., Jr., 2 Gil, D. R„ 9 Gillespie, T. L., 369-376 Gold, W. M., 327 Goldberg, S. J., 295-304, 305, 306 Gorlin, R., 231, 233, 234 Gowdey, C. W., 315, 316 Gribbe, P., 186 Grobstein, C., 12 Gross, R. E., 2 Guyton, A. C., 318

H Hajdu, S., 136 Hales, S„ 163 Hall, V. E. H., 181-183 Hallerman, F. J., 186, 188, 190, 192, 265, 267

CONGENITAL

436

Hamburger, V., 18, 29, 30 Hamilton, H. L., 18, 29, 30 Hatcher, J. D., 313 Hawthorne, E. W., 176 Hay, R. E., 250 Heath, W. C„ 195, 196 Helmholtz, 407 Herrick, J. F., 274 Hill, A. V., 150 Holt, J. P., 191, 192, 197 Hubbard, J. P., 2 Hufnagel, C. A., 2 Hugenholtz, P. G., 201-230, 265, 267, 270, 271, 305-307 Hunter, 1

HEART

DISEASE

Morris, J. A., 75 Moss, A. J., 101, 102, 122 Mullins, C. B., 163-179, Murray, J. F., 309-319, 345, 346 N Naeye, R. L., 131 Nelson, C. V., 373 Nordenstrom, B., 187 Nylin, G., 2 O Orts-Llorca, F., 9 Osler, W., 1 Osypka, P., 434

Hurwitz, R. A., 331-344 Ison, E. L., 176

I

J Jacobson, B., 24 Jarmakani, M. M., 247-263, 266 K Kemper, W. S., 377-382 Kennedy, J. W., 227 Kirkwood, R. E., 126 Knopp, T. J., 195 Koch-Weser, J., 143 Kolin, A., 383-405 Kramer, J. D., 296, 306 L Landis, E. M., 35 Langer, G. A., 136, 164, 181-183 Larsson, K. S., 25 Le Douarin, G., 43 Le Douarin, N., 43 Lees, M. H., 126 Levin, A. R., 247-263 Lillehei, C. W„ 2, 3 Linde, L. M„ 321-329, 345, 346 Lister, J. W., 333 Lloyd, T. C. Jr., 323, 325 Lorentz, H. A., 384 Lurie, P. R., 296, 306 M Macklin, C. C., 322 Mahon, W. A., 75 Mall, 1 Mason, D., 268 Matsuoka, Y., 229 McCrae, T., 1 Melmon, K. L., 133 Miller, D. E., 334 Miller, G. A. H., 185, 186, 219 Mitchell, J. H„ 163-179, 181, 182, 221, 222, 305 Mollier, S., 10 Mommaerts, W. F. H. M., 135-138, 164, 181, 182

Monroe, R. G., 229 Morgagni, 1

P Paff, G. H„ 34, 35 Parrish, D., 27 Patten, B. M., 34, 36 Peacock, T. B., 1 Plesch, J., 309 Podolsky, R. J., 143 Pryor, T. A., 409-418 R Rackley, C. E., 205, 219, 227 Rakusan, K., 115 Rapaport, E., 197 Rastelli, G. C., 190 Rawles, M. E., 11 Relman, A. S., 102 Ricchiuti, N. V., 136 Richards, D. W., Jr., 2 Roger, 1 Rokitansky, 1 Rosenblueth, A., 136, 175 Ross, J., Jr., 149-161 Roy, A., 102 Roy, C. S., 163 Rudolph, A. M., 101, 102, 105-118, 126, 131-133 Rushmer, R. F., 274 Ruttenberg, H. D., 331-344, 345

121,

S Saigado, C. R., 268 Sandler, H., 202, 205, 219, 228, 250, 267 Sanmarco, M. E., 188, 191, 267 Sarnoff, S. J., 136, 332 Schimpf, S., 124 Selvester, R. H„ 369-376, 407, 408 Simmons, D. H., 321-329 Sissman, N. J., 9, 37, 42 Solomon, J. C., 369-376 Sonnenblick, E. H., 143, 149-161, 181, 182, 219, 222, 226, 265, 270, 271, 306, 312 Spach, M. S., 247-263, 265-267, 269, 347368 Spallanzani, 1 Spann, J. F., Jr., 181 Stalsberg, H., 10 Starling, E. H„ 59, 164 Starzl, T. E., 334

NAMK Stauffer, W. M., 409-418 Stephens, N. L., 300 Sturm, R. E., 419-434 Swan, H. J. C., 185-200, 219, 265, 267-270, 300, 345 Taccardi, B., 351, 369, 370, 375 Talner, N. S„ 119-129, 131, 132 Taussig, H. B., 2 Tooley, W. H., 102 Tsakiris, A. G., 124 Van Citters, R. L., 273-288, 305, 307, 331344, 377-382 Van Mierop, L. H. S., 27-36, 37, 44 Vassalle, M., 336, 337

INDEX

437

Von Anrep, G., 174 Von Haller, 1 W Wagenvoort, C. A., 110 Wagner, H. R„ 201-230 Wahlund, H., 296, 303 Warner, H. R., 409-418 Watson, N. W., 377-382 West, J. B., 321 Whitehouse, M. W., 24 Wilcken, D. E. L., 231 Wolff, H. P., 124 Wood, E., 306, 345, 346, 407, 408, 419-434 Wright, G. W., 325 Yuan, S„ 115

SUBJECT INDEX

A Acetyl strophanthidin, see Digitalis drugs Acid mucopolysaccharide, see Mucopolysaccharide, acid Acidemia in neonate catecholamines and, 68, 70-73 metabolic influences and, 66, 69-71, 73 oxygen tension and, 79-82, 96, 97, 102 ventricular function, 66-73 Acidemia, metabolic ventricular function and in newborn, 66-71, 73, 79-82, 96, 97 Acidosis catecholamine release in, 324 circulatory effects of, 120, 121 pulmonary circulation and, 111-113,323325 ventricular function and, 68, 69, 81, 82 Actin cardic contractility and, 136, 143 myosin and, 182 Adams-Stokes seizures AV block and, 336, 337, 341, 342 Adrenergic nerves heart effects of cocaine and, 37 heart failure and, 289-294 contractility and, 289-291, 293, 294 dopamine and, 289 norepinephrine and, 289, 291-294 tyrosine hydroxylase, 289-291 heart norepinephrine in, 8 ventricular contraction and, 136, 138 Aldosterone urinary excretion of, 24, 127 Alkalosis pulmonary circulation and, 324 Allantoic artery blood pressure of chick embryo, 29, 36 Amniotic fluid, 13 Anemia blood viscosity and, 314-317 blood volume in, 309, 310 cardiac failure and, 109, 110 cardiac function and, 309-318 peripheral resistance in, 313, 314 sickle cell, 345 Angiography, 266, 267, 271 ventricular volume and, 185 indicator dilution method for, 185, 188, 189, 192, 193, 198, 199

videometry computer processing and, 419-434 Angiotensin myocardial effects of in newborn, 82, 83 Anomalies, cardiac, see Congenital heart disease Aorta blood flow in exercise and, 280 fetal blood flow in, 49, 50, 52-54 Aortic arch anomaly sodium salicylate in embryonic heart, 19, 43 Aortic arch reflex in newborn, 92 Aortic atresia, 107, 120 Aortic regurgitation, 183, 202, 207, 214, 217, 226 Aortic stenosis, 202, 207-214, 217, 227-229, 267 muscular subvalvar, 202, 207-209, 214 valvular, 202, 207-214 Arrhythmia, 266, 267 Arterial oxygen tension cardiac function and, 79-83 circulatory effects of, 73-79 Arterial pressure in chick embryo, 29-34, 36 telemetry of, 378-381 Artery, pulmonary constriction of, 115 pressure in, 131 birth changes in, 110-114 Artery, umbilical, 133 blood flow in, 105, 106 Asphyxia during birth, 120, 121, 126, 127 ventricular function and, 66 Atria of newborn, 87 Atrial septal defect, 346 electrocardiography of, 351, 363 exercise capacity in, 299-301 secundum type of, 202, 225 Atrioventricular sulci embryonic heart and, 9 Atrium volume of angiographic measurement of, 186, 190, 191 Atrium, left 439

440

CONGENITAL

pressure in, 106, 107, 120, 124 fetal, 49 Atrium, right pressure, in, 111, 112 Atropine heart rate and in newborn, 85, 90 Autonomic nervous system circulation and fetal, 83-94 newborn, 81-94, 97 fetal ventricular function and, 83-91 Autoradiography of chick embryonic heart, 9-12

B

Baroreceptors in newborn circulation and, 92-94, 97 ventricular function and, 94 Beta adrenergic blocking cardiac failure and, 109 contractility and, 307 exercise and, 240 heart and, 37, 240 Biplane angiocardiography, 201-209, 217, 225-227 computer analysis and, 205-207 ventricular function and, 166-168, 176 Birth changes, 131 circulatory, 65, 92-94 fetal, see Fetus myocardial, 119 Blood carbon dioxide fetal, 48, 54, 55 Blood flow cephalic in newborn, 81, 83, 84 pulmonary fetal, 47-50, 52 regional exercise and, 305, 306 hypoxia and, 101 in fetus and neonate, 47, 49, 50, 54, 55 splanchnic fetal, 56 systemic fetal, 48-50 Blood gas tension ventricular function and in newborn, 66 Blood oxygen tension, 106-108, 111-113 fetal, 48-56 in newborn, 79 ventricular function and, 69, 73, 76-79, 96 Blood pH cardiac contractility and, 70, 71 fetal, 48, 106 newborn, 111 Blood pressure chick embryo, 27-36 fetal, 49 Blood viscosity blood flow and, 314-317 Bradykinin, 107, 108, 113

HEART

DISEASE

Bulboventricular sulci embryonic heart and, 9 C Calcium ion contractility and, 136, 142, 143, 145, 181 myocardium effects of in newborn, 82 Capillaries density of, 115 Carbon dioxide tension in newborn, 73, 78 Cardia bifida microsurgical production of, 10, 11 Cardiac function, see Heart, Atria, Ventricles, etc. Cardiac glycosides, see Digitalis drugs Cardiac jelly acid mucopolysaccharides and, 17, 25 morphology of, 42, 43 Cardiac muscle, 307 contractile dynamics of, 149-153 contractile element in, 153-155 Hin model of, 150, 151, 158-160 rate factors in, 150-153 contractility of, 102, 103 mitochondria and, 307 sarcomere length in, 159 Cardiac output, 124-127, 131, 135 anemia and, 309-318 control of in newborn, 59-66, 68, 69, 71-83, 87, 8991, 97 heart rate and, 334-336 in fetus and neonate, 47, 50, 52-56 in newborn, 60, 61, 68, 71, 73, 76, 79, 84, 87, 94 metabolic acidemia and in newborn, 63, 76, 81, 85-87, 94, 96 Cardiac size, 269, 270 Cardiogenic crescent, 7, 8, 11, 12 Carotid sinus reflex in newborn, 84, 91-94, 97 ventricular performance and in newborn, 93, 94, 97 Catecholamines, 132, 133 biosynthesis of in fetal heart, 37-41 cardiac contractility and, 136, 142 cardiac failure and, 108, 109 fetal heart effects of, 37-42 neonatal heart and acidemia and, 68, 70-73 tyrosine hydroxylase and, 37-41 ventricular function and in acidemia, 70-73 see also Norepinephrine, Isoproterenol Catecholomethyl transferase heart norepinephrine, and, 41 Catheterization, heart computer analysis during, 409-418 Cell differentiation in embryonic heart, 7-12, 43 Cell growth in embryonic heart, 7-13

SUBJECT Choindroitin sulfate sodium salicylates and in embryonic heart, 24, 25 Cineangiocardiography flow measurement by, 249, 250 Circulation, cephalic fetal, 56 Circulation, coronary adaptation of, 115 exercise and telemetry studies of, 280-282, 287 insufficiency of newborn, 65 myocardium and, 115, 116 Circulation, fetal, 133 birth changes in, 105-116 dynamics of, 119 Circulation, hepatic fetal, 52 Circulation, mesenteric exercise and telemetry studies of, 274, 282-287 Circulation, newborn autonomic control of, 83-94 baroreceptor influences on, 92-94 cardiac failure in, 119-127 circulatory birth changes, 105-115 fetal circulation and, 105-107 heart function in, 59-97 myocardium and, 119-127 ventricular function in, 65, 66 Circulation, placental, 50, 54, 55, 105, 107 Circulation, pulmonary, 49 blood flow, 108, 110, 111, 113, 119-121 blood volume in, 120, 121 communications with systemic, 110 congestion of, 119-122 in neonate, 105, 107-113 pulmonary hypertension, 269 genesis of, 326, 327 hemodynamics of, 325, 326 pulmonary vascular resistance, 119, 120, 131, 133, 321 in neonate, 105, 107-114 regulation of, 321-328 chemical factors in, 322-325 drug effects on, 327, 328 mechanical factors in, 322, 325 small vessels of muscle in, 131 vasculature of, 131, 133 vasoconstriction in, 111, 112 vasodilatation in, 133 Circulation, regional exercise and telemetry studies of, 273-287 fetal, 54, 55 redistribution of exercise and, 273, 274, 286 Circulation, renal exercise and telemetry studies of, 273, 274, 284-287 fetal, 56 Circulation, umbilical, 56

INDEX

441

Circulation, uteroplacental, 48-50, 52, 54, 55, 107 hyperbaric oxygen effects on, 48-50, 52 Coarctation, 125, 202, 227 Computer data processing and videometry angiographic hemodynamic investigations, 419-434 biplane roentgen videodensitometry, 419-428 cardiac output and, 425-428 congenital disease and, 424, 425 indicator dilution technique and, 419428, 434 mechanics of, 420, 421 biplane roentgen videometry, 419, 428433 cardiac output and, 429, 430 volume measurement and, 430-433 Computer analysis, on-line during heart catheterization, 409-418 dye dilution curve analysis, 413-415 editing, 417, 418 pressure analysis, 412-417 time-sharing, 409 Congenital heart disease cellular basis of, 7, 8 clinical manifestations of, 105 ECG study of, 347-367 embryonic basis of, 17, 19, 23 exercise capacity in, 295-303 heart rate in, 295 history of, 1-4 myocardial function in, 201-229 volume overload and, 207, 214, 228, 229 Congestive heart failure, 108-110 adaptation to, 124-127 biochemical alterations in, 119, 123, 124, 127 digitalis refractive, 126 in newborn, 66, 119-127 in utero, 131, 132 left-sided, 119, 124-126 right-sided, 124, 131, 132 symptomatology of, 119-123 Conoventricle chick embryonic heart and, 9 Contractility, 265, 267-270, 306, 307 adrenergic nervous system and, 289-291, 293, 294 propranolol and, 345, 346 Contraction mechanics of in intact heart, 149-160 Coronary circulation, see Circulation, coronary D Depressor reflexes in newborn lamb, 93 see also Carotid sinus Dextrocardia embryogenesis of, 8-11

442

CONGENITAL

Digitalis drugs actions of, 133 inotropic effects of, 233 myocardial effects of newborn, 82, 83 pulmonary circulation and, 328 DNA synthesis in embryonic heart, 9 Dopamine, 293 Ductus arteriosus, 105, 107, 113, 131-133 fetal blood flow in, 49-55 methods for study of, 48 resistance of, 113 shunting through, 105, 107 Ductus arteriosus, patent, 110, 113, 122, 125, 346, 424 Ductus venosus, 105 Dye dilution techniques, 267, 268 E Electrocardiography computer analysis of, 369-375 congenital heart disease and, see specific disorders exploratory, 347-367 isopotential surface maps in, 347-367, 369 mathematical model of, 369-375 respiratory effects on, 348-353, 361-363 simulation of, 369 thoracic geometry and, 373 total body ECG mapping, 369-375 see also Vectorcardiography Electromagnetic flowmeters, see Flowmeters, electromagnetic Embryonic heart anomalies of X-rays and, 43 atrial development, 11 autoradiography of, 9-12 blood pressure in, 27-36 cardiac jelly in, 17, 25, 42, 43 cardiogenesis, 12-14 cell growth in, 7-14 DNA synthesis in, 9 endocardial cushions in, 34-36 endocardium, 17, 41-43 endoderm and, 12 epimyocardium, 10, 17, 43 growth inhibition in sodium salicylate and, 22 hemodynamics of, 44, 45 innervation of, 8 isotopic labelling in, 17-25, 43 mesoderm of, 9, 11, 12 morphogenesis cellular basis of, 7-14 mortality in sodium salicylate and, 19, 20, 23-25 mucopolysaccharide synthesis in, 17, 19, 22-25 oxidative phosphorylation in, 24 potassium ions in physiological effects of, 12, 13 sodium salicylate effects on, 17-25

HEART

DISEASE

tubular heart, 17 sodium salicylate and, 18 Endocardial cushion tissue X-ray effect on, 43 Endocardial fibroelastosis, 214, 228, 269-271 Epinephrine cardiac failure and, 108, 109 fetal blood pressure and, 44, 45 Exercise heart response to, 234-242 regional blood flow and, 273-287 sympathetic role in, 235-242 valvular disease and, 269 ventricular force-velocity relation and, 269 Exercise tests blood flow in, 300-303 congenital heart disease and, 295-303 heart rate and, 295-303 Extrasystoles contractile strength and, 136 F Fetus cardiac sympathetic of, 7, 8, 37-42 changes at birth cardiac output, 101 circulation, 105-115 ductal flow, 101, 102 umbilical blood flow, 101 circulation in, 47, 52-54 regional, 47-56 heart innervation of, 7, 8 norepinephrine in, 7, 8, 37 Fiberoptic techniques, 201, 202, 207-209, 217-219, 225-227 Fibroelastosis, 214, 228, 269-27] Fistula, arteriovenous, systemic, 120, 123 Flowmeters, electromagnetic, 94 alternating magnetic feed type, 383, 384 catheter flowmeters, 400, 401 constant magnetic feed type, 383 evaluation of, 383, 404 experimental use of, 391-404 external magnetic field method, 396 fetal circulation and, 47, 48 low-cost types of, 398-400 miniaturization of, 391 multiple flowmeter implants, 396-398 physical principles of, 383 Flowmeters, ultrasonic, 407, 408 calibration of, 407, 408 effect of hematocrit on, 408 thermal effects of, 408 Foramen ovale, 106, 107, 111, 112, 120, 124, 131 Frank-Starling mechanism, 59-63, 136, 163, 164, 168, 173, 175-177, 226 cardiac muscle and, 152-155 exercise and, 242 G Ganglionic blocking agents fetal circulation and, 48

SUBJECT ventricular performance and in newborn, 85, 90, 91, 94, 97 H Heart arterial oxygen tension and, 79-83 contraction of, 149-160 see also Ventricles, contraction of Frank-Starling principle in newborn, 59-63 function of, see also Ventricles complete heart block and, 331-343 isoproterenol effects on, 37 neonatal, see Circulation, newborn norepinephrine content of, 37-42 papillary muscles function of, 66 sympathetic innervation of, 37-42, 44, 45 Heart block, complete autonomic control in, 331-342 drug effects in, 338-342 experimental production of, 332, 333 heart failure and, 342 heart function in, 331-343 Heart failure and nervous system, see Adrenergic nerves Heart rate autonomic effects on, 85 cardiac output and, 334-336 complete AV block and, 331-343 contractile strength and, 136, 139, 143, 233 exercise and, 235-239, 295-303 tachycardia in newborn, 122, 123, 126 ventricular function and in newborn, 68, 71-74, 78-80, 84-87, 91-94 Hematocrit, see Anemia Hexamethonium cephalic hypotension and, 90 Hypercapnia ventricular function and, 66 Hyperthyroidism circulatory effects of, 120, 123 Hypothalamus heart function and, 339 Hypothyroidism circulatory effects of, 121 Hypoxemia, 102 Hypoxia fetal, 50 peripheral resistance and, 313, 314 pulmonary circulation in, 322-325 regional blood flow and, 101 ventricular function and in newborn, 66, 73, 78-82, 96, 97, 120, 121 I Indicator dilution methods ventricular volume angiographic method and, 185, 188, 189, 192, 193, 198, 199

INDEX

443

Isoproterenol atrial septal defect and, 219, 225, 226 heart effects of, 37 ventricular effects of, 233, 239, 240 see also Catecholamines K Kinins circulatory role of, 107, 108 lungs and, 133 L Lactic acidemia, 120, 121 Lungs circulation in, see Pulmonary circulation expansion of in term fetus, 75, 76 fetal, 105, 107 kinins and, 133 mechanics of, 122, 127 positive pressure ventilation of, 120 in newborn, 73, 76 respiratory distress, 121, 122 ventilation in fetus and neonate, 48-50 ventilation-perfusion ratio in, 112 M Metabolic rate blood flow and fetal, 47 Mitral atresia, 120 Mitral regurgitation, 202, 207, 214, 217, 226, 227, 229, 424 Mitral stenosis, 202, 269 Monoamine oxidase heart norepinephrine and, 40, 41 Mucopolysaccharide, acid synthesis of in embryonic chick heart, 17, 19, 22-25 Muscle, cardiac cinefluorographic study of, 166-168, 176 contractile element of, 137, 142, 144-147 contractility of, 137, 139, 141, 142, 144, 146, 147 action potential duration and, 143, 147 active state and, 137, 138, 143, 144 mechanics of, 135-147 contraction of, 182, 183 initial fiber length and, 139, 141-147 load responses, 137-144 mechanical analysis of, 139-147 membrane depolarization and, 139, 142, 143 myofilament role in, 142-147 staircase phenomenon in, 135, 136 Starling's principle, 135, 136 velocity characteristics of, 138, 141, 144 dp/dt in, 139, 141-145, 147 force-velocity relations in, 137, 145 excitation-contraction coupling in, 142147 heart production of, 136 hypertrophy of, 181, 182

444

CONGENITAL

inotropic states of, 136-138, 141-144, 147 mechanics of, 163-165, 169, 171, 172, 175, 183 membrane potentials of, 142, 143 refractory period of, 136 series elasticity of, 137, 144-147 ultrastructure of elastic components of, 182 Hill model of, 182 work performance of, 139, 142 Muscle, skeletal contractile strength of, 137 Myocarditis, 214, 228 Myocardium, ventricular, see Ventricle Myosin cardiac contractility and, 136, 143 N Norepinephrine, 289, 291-294 embryonic blood pressure and, 44, 45 fetal heart and, 7, 8 heart content of, 37-42 inotropic effects of, 37, 233 ventricular function and, 175-177 in newborn, 66, 71, 73, 82, 83 see also Catecholamines O Ouabain, see Digitalis drugs Oxygen, hyperbaric fetal circulation and, 50-54 uteroplacental circulation and, 48, 5054 see also Hypoxia P Paired electrical stimulation inotropic effect of, 233 Papillary muscle cardiac contractility and, 136, 137, 146, 147 see also Cardiac muscle Parasympathetic nervous system in newborn, 85, 90 Parenchyma, liver, 105 Peripheral resistance exercise and, 269 pH ventricular performance and, 66, 67, 69, 71-73, 76-82, 96, 120, 123, 124, 126, 127 Physical fitness tests for, 295-303 Placenta, see Circulation, placental Potassium cardiac arrest and, 305 cardiac contractility and, 143 heart function and, 337 in chick embryo, 12-14 Propranolol, 289-291 contractility and, 345, 346 heart effects of, 342 see also Beta adrenergic blocking

HEART

DISEASE

Pulmonary artery pressure, see Circulation, pulmonary Pulmonary atresia, 107 embryonic development and, 19 Pulmonary blood flow, see Blood flow, pulmonary Pulmonary circulation, see Circulation, pulmonary Pulmonary edema pulmonary capillaries and, 325 Pulmonary hypertension, see Circulation, pulmonary Pulmonary insufficiency, 131, 132 Pulmonary stenosis, 202 dynamics of, 257 exercise capacity in, 299, 300 Pulmonary stenosis, congenital, 115, 116 Pulmonary vascular resistance fetal, 48-50, 52-55 see also Circulation, pulmonary Pulmonary veins, see Veins, pulmonary Pulmonic regurgitation, 119, 120 B Regional blood flow, see Blood flow, regional Renal circulation, see Circulation, renal Resistance, peripheral, see Systemic resistance S Salicylate effects on embryo heart, 17-25, 43 Septal defects, ventricular, see Ventricular septal defects Shunts aorta-pulmonary experimental studies of, 108, 109 intracardiac exercise capacity in, 299-301 mechanisms of, 247-263 pulmonary hypertension and, 327 left-to-right, 108, 109, 111, 113 atrial, 119-124 premature infants and, 120 mechanisms of, 105, 108, 109, 111, 112 Sodium cardiac contractility and, 142, 143 Starling mechanism, see Frank-Starling mechanism Sympathetic nervous system beta adrenergic effects of, 242 circulation and in newborn, 84 complete AV block and, 331-339 exercise role of, 238-242 heart effects of, 238-242, 331, 332 tonic activity of, 342 vasomotor tone and fetal, 48, 50 ventricular performance and, 122-127 Systemic blood flow, see Blood flow, systemic

SUBJECT Systemic resistance, 48-50, 54-56, 108 anemia and, 313, 314 arterial oxygen tension and in newborn, 66 cephalic hypotension and, 91 fetal, 48-50 hypoxia and, 313, 314 Systemic vasoconstriction, 85 T Tachycardia in newborn lamb, 73, 78, 79, 85 TEAC cephalic hypotension and, 90 Temperature contractility and, 139, 143 Teratogenic effects of sodium salicylate on embryonic hearts, 17-19, 23-25, 43 Tetralogy of Fallot, 266 ventricular dynamics in, 247, 250 Thermodilution techniques, 267, 268 Transposition of the great vessels, 120, 121, 123, 127 Tricuspid regurgitation, 119, 120, 132 Truncus arteriosus communis, 107 Tyrosine hydroxylase, 293 V Vagi myocardial function and in newborn lamb, 85 Vagotomy in newborn Iamb heart rate and, 85, 90 Valvular regurgitation, 186, 187, 191 Vectorcardiography, 408 mathematical model of, 369-375 see also Electrocardiography Veins, pulmonary blood flow in, 121-123 blood p H in, 112, 113 blood pressure in, 121, 124-126 oxygen tension in, 113 Veins, systemic congestion of, 119-124, 127 Veins, umbilical blood flow in, 105, 106 blood pressure in, 105 methods for study of, 48, 50, 52 Velocity of muscle fiber shortening newborn myocardial performance and, 60,97 Vena cava, inferior fetal circulation and, 52 Venous return Starling's law and, 136 ventricular function and in newborn lamb, 61 Ventilation in newborn lamb, 73, 76-80 Ventricle, left blood flow in, 115, 116

INDEX

445

cardiotonic agents and newborn, 82, 83 d p / d t in newborn, 60, 61, 71, 81, 82, 85-87, 89, 94 end-diastolic pressure newborn, 60-68, 71, 80, 82, 85-87, 94 function of biplane angiocardiography of, 201-209, 217, 225-227 congenital heart disease in, 201-229 fiberoptic hemoreflection technique for, 201, 202, 207-209, 217-219, 225227 force-velocity relationships in, 219-227 Frank-Starling mechanism in, 226 wall force and, 219-221, 227, 228 hypertrophy of, 116 hypoplasia of, 106, 107, 124 myocardium of, 63, 66, 87 weight of, 113 Ventricle, right blood flow in, 115 end-diastolic pressure in, 111, 112 filling pressure in, 122 hypertension of, 115, 116 myocardium of, 115, 116 obstruction of, 123 outflow obstruction of, 113, 116 output of, 105 pressure in, 110-112 weight of, 113-115 Ventricles acidemia influence on, 66-73 anemia effects on, 309-318 asystole of, 336, 337 autonomic effects on, 83-91 catecholamine influence in acidemia, 70-

73

contractility of, 231-242, 265, 268-270 in newborn, 65, 66, 68, 70, 71, 81, 83, 84, 87, 90, 91, 94 mechanical analysis of, 139-147 contraction of, 149-160 Anrep effect in, 173-177 artificial stimulation of, 333, 334 autoregulation and, 168, 172-177 Bowditch phenomenon in, 181 determinants of, 163-177 d p / d t in, 144, 145 force-velocity relations in, 156-158, 165, 166, 231-242, 312 hypertrophy and, 181, 182 inotropic mechanisms, 157, 158 ionic control of, 181 isovolumetric, 156 nervous control of, 331-343 synchronism of, 333, 334 wall stress and, 159 dimensions of determination of, 231-242 disease, 269 Young's modulus in, 201, 205. 214. 228 ejection rate

446

CONGENITAL

in newborn, 60, 62, 63, 66, 68, 69, 71, 94 end-diastolic volume of contractility and, 142 enlargement of, 120, 122 excitation of ECG evidence of, 348, 349, 364, 367 exercise and, 234-242 filling pressures of, 125, 126 Frank-Starling mechanisms in, 59-63 hypertrophy of, 109, 127, 132, 133 hypoxia and, 81-83, 97 inotropic influences on, 233 inotropic responses in newborn, 87-90, 97 metabolic factors affecting newborn, 59-97 muscle of, see Cardiac muscle myocardium of catecholamines and, 37-42 output of Bowditch effect, 172, 173, 176, 177 determinants of, 163-165, 171, 172, 175-177 Frank-Starling mechanism and, 163, 164, 168, 173, 175-177 oxygen supply of, 110 performance of failure of, 119-124, 127 power of, 163, 164, 169, 171-177 pressure-volume loops of, 250 rate of autonomic control of, 331-342 complete AV block and, 331-343 reflex control of

HEART

DISEASE

in newborn, 61, 83-96 shunting mechanisms in, 247-263 sympathetic effects on, 235-242 ventricular function curves, 163, 164, 169177 in newborn lamb, 63, 68, 80, 81, 87 volume of, 59 angiographic method for, 185-192, 198, 199 effects of contrast medium on, 265-267 fiberoptic method for, 191, 192 indicator dilution method for, 185, 188, 189, 191-199 measurement of, 185-199 silver clip technique, 268 work of, 163, 164, 169-177 measurement of, 186 see also Muscle, cardiac Ventricular septal defect, 107, 110, 111, 113, 122, 125, 126, 202, 207, 214, 217, 227229, 270, 346, 424 cardiodynamics of, 247-263 embryonic development and, 19, 23, 25, 43 Videometry angiography and computer processing and, 419-434 W White blood cells kinins and, 133 X X-ray effect on chick heart embryo, 43