Stimulations, provocations and new frontiers

Panel Discussion

Stimulations, Provocations andNew Frontiers*

CHAIRMAN : ALFRED SOFFER, M.D., F .A .C .C ., Chicago, Illinois

PARTICIPANTS

IRVINE H . PAGE, M.D ., F .A .C .C ., ClevelandEUGENE BRAUNWALD, M .D ., F .A .G .C .

Bethesda

IN A recent review of The Spontaneous Regres-sion of Cancer by William Boyd, the book

reviewer (M. Bohrod) stated, "There follows achapter of speculation by far the most interestingand important part of the hook . Fortunately,we no longer think speculation can be neglectedin science ."Dr. Walton Lillehei described the discussions

in this symposium as "thought-provoking theo-ries, ideas and personal viewpoints of distin-guished scientists based upon their extensive ex-periences but not necessarily considered provedor provable by currently available information."We believe that this type of symposium is a eon-

VOLUME 20, NOVEMBER 1967

ALVAN R. FEINSTEIN, M.D ., New Haven, Conn .JOHN W . KIRKLIN, M .D ., F.A .C .C .

Birmingham, Ala .

structive innovation in cardiologic scientific ses-sions, and we trust that this will be the first ofmany comparable panels . There were only twostipulations for this session : (1) the lecturersshould be distinguished investigators with amajor interest in cardiovascular disease, and (2)presentations should be broader in scope andintent than the usual report . Presumably, theemphasis this year and in succeeding years willbe upon creative concepts in pathogenesis, diag-nosis and treatment. However, we envision alsothe inclusion of such topics as postgraduate edu-cation and ethical implication of investigation aswell as a variety of other provocative subjects .

The first speaker, Dr . Irvine Page, represents that rarity in internationalscientific circles, a widely acclaimed investigator in both the laboratory andclinical milieu who has not divorced himself from the sociologic, politicaland economic aspects of medicine, particularly as these affect research andteaching . Distinguished editor, researcher and teacher, Dr . Irvine Pagewill open the discussion .

Maintenance of Skepticism in an Affluent WorldsIRVINE H. PACE, M.D ., F.A .C .C .

STRICKEN Austrian Lad Seeks Rand Miracle-"Spare Hearts Ready Soon"-" Medicine

Now on Verge of Electronic Upheaval""So-ciety (Biosis) to Promote a Longer Life Span"-"America's 10 Best Hospitals"-"But EverybodyCheats" ; and so the medical headlines go in ouraffluent society . The abundance no one can

703

doubt, and in the past 20 years some of it hasrubbed off onto medicine, as well as, of allthings, research .

The dark side is that abundance usually ofitself creates an atmosphere of irresponsibility .There is neither a wolf at the door nor one in theneighborhood ; the economic urge is dulled, we

* Presented at the 16th Annual Meeting of the American College of Cardiology in Washington, D.C., Feb. 17, 1967 .f From the Research Division ofthe Cleveland Clinic Foundation, Cleveland, Ohio .

704

Panel Discussion

are satiated by Loo much food, too much enter-tainment, too much to read, too many children-indeed, too much of almost everything butbrains . Material affluence distracts from man'screative urge, the pressure which makes a manneed to contribute to what is euphemisticallycalled "progress ." But without "progress" it ishard to think of man's being worth much .But what about skepticism in this affluent

world? Skeptics are usually unpopular for sev-eral reasons, originally perhaps because theydoubted the truth of religious doctrines . Theywere believed to be cynical, their thinking outof step with the crowd . Too often the skepticexamines personal morality in the modern senseof being inclined to suspend judgment . Thecontrast with the confident activist is the morestriking because the news media so quickly andeffectively broadcast the latter's positive andconvincing promises of Utopia . The doubtingThomas appears to cling to the status quo and toresist every new idea-in short, a professionalwet blanket . The very idea of skepticism hasbecome a rapidly weakening strand in the pat-tern of current thinking . This is especially truein Communist countries .

Several relatively modern inventions workagainst healthy reservation of judgment, chiefamong which is the growing confidence in thewisdom of cornrnittees . Thee fact is, committeeshave great merit but serious weaknesses as well ;the skeptic calls your attention to the dangers ofthe lack of preparation, the often inept system ofappointing committee membership, the naturaldesire for consensus, the overpowering of theweaker by the louder and stronger . Despitethese pitfalls, most problems seem to be put inthe hands of committees for solution .

Another aspect compounding the effects ofaffluence is the growth of government . Govern-ment, whether federal, state, or local, is imping-ing on almost every phase of our lives, rangingfrom income tax and control of practice to theethics of experimentation . Forty years ago wewere not conscious of the effect of Washingtonupon us ; now if Washington isn't innovating,thrusting, targeting, incrementing, or monitor-ing, I wonder what it must he up to-

I will be more specific . For example, medi-cine has never seen a more turbulent era, withattacks coming from all sides . It is open seasonon the doctor, although I am sorry to admit thatlie has largely himself to blame. While he as-sumes the right to control and police himself, hedoes it halfheartedly . He is expected to main-tain dignity and decorum, especially in his rela-

tions with the press . I need hardly comment onhis failure to do so . With all his faults, whenyou need him, there is still nothing like him ! Heneed not go the way of all flesh . Healthyskepticism, openly expressed, is his protection ;it is a weapon he must never throw away_

America's Hospitals: Here is an example ofwhere a little skepticism would have avoidedsome very disturbing and potentially harmfulresults . "A Jury of Experts Picks America's 10Best Hospitals" appears in the Ladies Home Jour-nal (February 1967) . The article has the edify-ing opening, "If I were sick and had to go to ahospital, there arc only a few places in thecountry I'd trust myself to . You could almostcount then, on both hands ." Incredibly, thisstatement cones from Dr . John Knowles, direc-tor of the Massachusetts General Hospital .Guess what hospital was at the top of the 10 bestas selected by a jury of 10 experts! The juryalso found that at best only two to three percentof our hospitals provide the kind of care thesemen want for themselves . The article then liststhe dire happenings in hospitals and so indictsthe majority of them by implication . The ex-perts kindly conceded that very occasionally asmall hospital could be excellent . They recom-mend the public make a beeline for a largeteaching hospital when ill, and only 17 per centof all hospitals fit this description . I am certainthat these are men of wisdom but equally certainthat they showed little of it by allowing theirselections and advice to be used as another attackon medicine . The question they were asked islike asking who is the most beautiful woman inthe world! Dr. Knowles, I am sure, would seethe trap in trying to answer this one .

Another tangential attack is highlighted by alead in Life Magazine, "It's a miracle that wesave any of them," a statement by Dr. JohnGillespie of Georgetown University MedicalCenter, referring to their daily half-dozen car-diac arrests. And Dr. Geschichter adds, " . . .that at least one in every six drug doses is givenat the wrong time, in the wrong amount or tothe wrong patient ." While the purpose of theseinterviews was to point out the need for archi-tectural redesign of hospitals, still the public isleft with the idea that all hospitals are prettydreadful and dangerous places where disasteris constant and its handling is miserable .

Announcing Scientific Discoveries : A differentproblem needing skeptical analysis is the currenttrend of announcing scientific discoveries in thelay press before they are made or after perform-ing the first experiments . A definite date (1970)

THE AMERICAN JOURNAL OF CARDIOLOGY

was set, for example, when artificial hearts wouldbe implanted at a rate of about 100,000 a year ata cost of $5,000 each . Systems analysis led, 1be-lieve, to this definitive statement . A grant inaybe announced publicly by a congressman tellingjust what will be discovered and how it will createa "breakthrough" to cure still another disease .This"forward thinking", if I may call it such, canbe an unadulterated disaster for truly creativeresearch . No good research man would confi-dently tell you what he is going to discover. Thenature of research is such that this is impossible .

Federation in Medicine and Research : Anothersubject deserves substantial dragging of the feet-the programs which insure creeping fed-eralism . I agree that government must play avital part in the conduct of medicine and re-search, but every step toward more participationmust be examined with healthy skepticism .Currently, there is an overwhelming tendency tobe influenced by the power, status and moneyassociated with government . Government is aninstitution and as such can supply a moralitythat supersedes any personal one . The impliedthreat, if you don't do it they will, seems to be theopening gambit in most discussions of healthlegislation . The other is that no individual can,or should, speak disparagingly of the well inten-tioned legislation already passed . Or that eye-brows should be raised when it is announcedthat, "'The faith that money can move moun-

Stimulations and Provocations

705

tains, reach the planets and cure man's ills hasbeen amply justified . Let the scoffers explainotherwise our successes against polio, measles,retrolental fibroplasia and glaucoma . . . ." Ifear that the speaker really meant money alonedid all these things. This makes me a scoffer .

These examples can he multiplied a hundred-fold, but rather I would again remind you thatskepticism is almost always an individual en-deavor . Committees and commissions are usu-ally free of it! The skeptic must realize that hisposture is not popular and must accept theslights and even at times being frozen out of thetaxpayer's largesse .

A National Academy of Medicine : As an anti-dote, I have suggested the formation of a Na-tional Academy of Medicine, beholden to noone, to tap the good brains of medicine in behalfof the public, the government and medicineitself. Such an organization could be a power-ful exponent of this guide and regulator of thefaculty of reason called skepticism . We mustkeep alive the core of people who are willing toexamine and question established authority, whowill not go along with the crowd even though itis made desirable, who believe that cheating ispersonal and dishonest, who will bear responsi-bility for exposing the shabby, even though thiswill make them unpopular . These are not theheroes of medicine, but without them there willbe no medicine worthy of its calling .

Dr. Eugene Braunwald is a phenomenon of our times . Chief of the Car-diology Branch and Clinical Director, National Heart Institute, Dr . Braun-wald became, at an unusually young age, a leading authority in a significantnumber of areas of cardiovascular hemodynamics and pharmacodynamics .It was inevitable that an investigator with such energy and insight shouldbecome the nucleus of a group of scientists who have become brilliant in-vestigators . Dr. Braunwald, in his editorial capacities, is displaying majorleadership in the guidance of cardiovascular publications in both the clinicaland basic spheres .

Insights into Cardiovascular Physiology Derived fromMuscle Mechanics*

EUGENE BRAUNWALD, M.D., F .A .C .C ., EDMUND H. SONNENBLICK, M.D., F .A.C.C .,JOHN Ross, JR ., M.D ., F.A.C.C . and JAMES H. GAULT, M.D .

N IMPORTANT challenge faced almost daily

estimation of this fundamental property of theby the cardiologist is the estimation of the heart is extraordinarily difficult or even impos-

contractile state of the myocardium in patients sible, unless contractility is severely com-with known or suspected heart disease . Clinical

promised . Even under these circumstances it` From the Cardiology Branch of the National Heart Institute, Bethesda, Md., 20014.


706

STOP

ISOTONICLEVER

-MUSCLE

~~TRA SDTRANSDUCER

a

AFTERLOA0-.

PRELOAO-,.jMIM

,avm

TIME (msec)

0

500

FIG . 1 . Top: Mechanical arrangement for the study ofheart muscle Bottom : Diagrams showing shortening andtension development in an aftertoaded contraction .

may be difficult to determine whether cardiacperformance is limited by an intrinsic abnormal-ity of the heart muscle, whether it is secondaryto an excess load such as may be imposed byhypertension or a valvular lesion, or whetherclinical disability results from some combinationof these two factors .

In an effort to solve this important and fre-quently encountered clinical problem, the cardi-ologist has naturally turned to the laboratoryand has frequently referred his patient to theclinical physiologist for detailed hemodynamicstudy . A variety of measurements can now bemade in the cardiac catheterization laboratoryin an attempt to evaluate myocardial contrac-tility . These include the volume of bloodejected by the heart, the ventricular end-dias-tolic pressure and more complex measurementssuch as the ejection fraction, the ventricular end-diastolic volume, the rate of ventricular pressurerise and the mean systolic ejection rate. Whileall of these variables are related to myocardialcontractility in some indirect manner, none is adirect expression of this fundamental property ofthe myocardium .

THE HEART AS A MUSCLE

While it is not yet possible to measure contrac-tility in the intact human heart, the principles

Panel Discussion

upon which this important measurement maybe based have been defined . An importanttheoretic consideration, which is necessary forthe uteasurement of myocardial contractility, isto consider the heart as a muscle rather than apump, as has commonly been done for manyyears . Extremely helpful methods for examin-ing the behavior of a muscle were provided bythe skeletal muscle physiologist early in thiscentury . The contractile activity of all musclemay be expressed externally in only two ways :shortening and the development of tension .Thirty years have now elapsed since A . V . Hillpresented what has been termed the most funda-mental property of muscle, the force-velocityrelation .' Hill showed in skeletal muscle thatthe velocity of shortening is inversely related tothe magnitude of tension development . Thatis, the greater the load the muscle is called uponto lift, the slower the velocity of shortening .

A number of investigators have extended theconcept of the force-velocity curve from skeletalto cardiac muscle .'? As a result of thesestudies, one of the most basic differences betweenskeletal and cardiac muscle has emerged . Skel-etal muscle has a single, essentially fixed forcevelocity curve, i .e ., force and velocity are alwaysrelated one to the other in the same manner .The contractile activity of skeletal muscle is in-creased simply by the recruitment of additionalmuscle fibers, while the contractility of eachindividual fiber remains constant . In contrast,the number of cardiac cells activated remainsconstant during each contraction . However,the contractile activity of the myocardium maybe shifted by changes in end-diastolic fiberlength and by changes in contractility, both ofwhich shift the myocardial force-velocitycurve

Force-Pelocity Curves: The top panel of Figure1 illustrates the mechanical arrangement utilizedfor study of isolated cardiac muscle . The pre-load determines the degree of the stretch on themuscle at rest, and the afterload is the weightthe muscle is called upon to lift during contrac-tion . Both the load lifted by the muscle and theextent of muscle shortening can be recordedwith precision . The bottom of the figure shows,in diagrammatic form, tracings of tension andshortening. Following activation of the muscle,tension develops until it lifts the afterload . Themuscle then shortens, as demonstrated by theupper curve .

Figure 2A shows a series of superimposed con-tractions . The, preload on the muscle was held


Fk;_ 2- A, relation between lertciondevelopment and shortening of thecat papillary muscle . As contrac-tion begins tension rises, as shownin the bottom tracing. As soonas the muscle lifts the afterload,it shortens, as show,' in the toptracings . The dashed lines rep-resent the initial velocity ofshortening . Both the extent andvelocity of shortening diminishas afterload is increased B, theverse relation between initial veloc-

ity of isotonic shortening and in-creasing afterload, the force-velocityrelation. From the cat papillarymuscle . C, the relation betweenpower (load X velocity) develop-ment of the papillary muscle andload . 1), the relation between work(load X displacement) developmentby the papillary murcle and load.(Reproduced by permission fromThe Myocardial Cell, pp. 185and 187. Edited by BRILLER,S. A. and CONN, H. L . Phila-delphia, 1960. University ofPnnnsvlvania Press .)



B

0

Col Popilloq Mutele Ip13mm

constant, but the afterload was varied progres-sively . When the afterload was relatively low,the velocity of shortening was high . However,as the afterload was raised progressively, thevelocity of shortening fell reciprocally . Then,when the load developed by the muscle wasplotted against the velocity of shortening, theforce-velocity relation shown in Figure 2B wasobtained . It is apparent that at a constantinitial length the external power (Fig. 2C) andwork output (Fig. 2D) of a muscle are also func-tions of the load .

Shifts in Force-Velocity Curves : It now appearsthat all variations in myocardial contractile ac-tivity can be expressed as shifts in the force-velocity curve . However, there are two funda-mental ways in which the force-velocity curvecan be shifted . Figure 3 shows a family of

LOAD (qml

INITIAL LENGTH CGISTANTIIImm)(pdOOE GAS)

INCREASING AFTERLGAG

LOAD

707

force-velocity curves obtained from a singlepapillary muscle ; each curve was obtained at adifferent preload, that is, with a different degreeof stretch on the muscle . Note that changingthe preload has altered the intercept of theforce-velocity curve on the horizontal axis, thatis, it has increased the isometric force developedby the muscle . However, these alterations inpreload have not altered the intrinsic velocityof shortening since all of the curves extrapolateto the same intercept on the vertical axis . Froththis it is apparent that an increase in initialmuscle length shifts the force-velocity curve byaltering the total force which can be developedby the muscle .

This type of shift in the force-velocity curvemay be contrasted with that obtained when apositive inotropic agent such as norepinephrine

708

L04D 19)

FIG . 3 . The effects of increasing initial muscle length on theforce-velocity relation of the cat papillary muscle . Initial veloc-ity of shortening has been plotted as a function of loadfor five different muscle lengths . The maximal velocityof shortening (Vma„) is essentially unchanged while themaximal force of contraction (P„) is augmented . Theinsert shows the places along the length-tension curvesat which these force-velocity curves were determined .(Reproduced by permission from Am. J . Physiol ., 207 :1330, 1964 .)

is added to the muscle, while the initial lengthis held constant. Figure 4 represents force-velocity curves before and after the addition ofnorepinephrine while initial muscle length washeld constant . Norepinephrine not only in-creased the force which the muscle is capable oflifting, that is, the intercept of the force-velocitycurve on the horizontal axis, but also increasedthe velocity of shortening of the unloaded mus-cle, that is, the extrapolated intercept on thevertical axis .

Causes of Changes in Contractile State and Myo-cardial Performance : An explanation for the in-crease in force development with increased ini-tial length is now available from the work of the1-Iuxleys . 7, s Figure SA shows a series of elec-tronmicrographs of skeletal muscle fixed at dif-ferent initial lengths, while Figure 5B showsschematic diagrams of the myofilaments . 9 It isclear that as the muscle fibers are stretched,going from I to 2 and then to 3 there is a diminu-tion in the overlap and therefore an increase in

Panel Discussion

LOAD ~m

FIG . 4. The effects of norepinephrine on the force-velocity rela-(ion of the cat papillary muscle . Both Vma , and Pa have beenincreased . (Reproduced by permission from Fed. Proc.,21 (Suppl .) : 975, 1962 .)'

the opportunity for reaction between adjacentmyofilarnents . In other words, the number ofsites at which the chemical reactions occur,which are responsible for the interaction be-tween the thin actin and the thick myosin fila-ments, increase as the muscle is stretched from1 to 3 .

Thus it may be postulated that an increase ininitial muscle length brings about an increasein the number of force-generating sites operatingeffectively in parallel in the muscle without achange in the qualitative character of the cyclicprocess at these contractile sites. Such a changewould be anticipated from a more advantageousoverlap of interdigitating contractile filamentswithin the sarcomere. When the muscle isoverstretched (Fig. 5A, 3 to 5), there is disen-gagement of myofilaments, a decrease in thenumber of force-generating sites, and a reduc-tion in the tension which can be developed bythe muscle . On the other hand, a change in thecontractile state, characterized by an increasein the velocity of shortening of the unloadedmuscle, would appear to result from an increasein the rate of cyclic force-generating processesat the contractile sites, without a change in thenumber of these sites .

A simple analogy for these events may be ex-pressed in terms of considering the sarcomereas a team of horses pulling a load (Fig . 6) . Inthis analogy, each horse represents a singleforce-generating site in the sarcomere . If theteam were not required to pull a load, then themaximal speed of the team, analogous to themaximal velocity of the muscle, would not beaffected by the number of horses comprising thelearn, as shown in Panel A, from 1 to 2 . If theteam were harnessed to a load, analogous to an

TIM AMERICAN JOURNAL OF CARDIOLOGY



7p9

A

afterloaded contraction, the speed with whichthe team could pull the load would be a functionof the number of horses in the team, as shownin Panel B, front 1 to 2 . Similarly, the velocityof shortening of an afterloaded muscle is a func-tion of its initial length and therefore of thenumber of force-generating sites . The forcewhich the team could exert on a fixed stake inthe ground would also be a function of the num-ber of horses in the team, just as the isometricforce of the muscle is dependent on its initiallength, as shown in Panel C . Thus, increasinginitial muscle length is analogous to adding morehorses to the team without altering the per-formance of any single horse . In contrast, ifthe number of horses in the team were left un-changed, analogous to maintaining musclelength constant, but if an inotropic stimulus suchas norepinephrine or digitalis were added, theneach individual horse would be capable ofrunning more swiftly, represented by a changein the general appearance of the horses . Themaximal running speed of the entire team, re-gardless of whether or not it were harnessed to

Fto- 5. The relatlmi bdurrn rnrenmne ten gilt and band pol,ne,i in slrlelal n .asde ij;,, u,/nrnu?. t'a„rl A (left) shows theband patterns as seen clectrornicroscopically ; Panel B Iri,,irl) shows the disposition of the thick and thin filamentswhich create these patterns. The vertical arrows in both panels denote the ends of the thin filaments which in-sert at the Z line at the left . Panel .1 (3) represents the sarcouere at the apex of the length-tension curve, i .e. atL„oz. In I and 2, sarcomere length has been progressively decreased, while in 4 and 5 it has been progressivelyelongated . Throughout, the A band remains constant in width . 'the,, placement of filaments to provide formaximal overlap is shown in B3 . Bt shows the sarcomere pattern near L, in the shortened muscle ; the I bandhas disappeared and a secondary dark band has been Counted at the center of the sarcomere, termed the Ccontrae-tiou band, which is due to the passage of thin filaments through this area as shown in HI . lit A, 4 and 5, an ex-panding H zone has appeared due to the withdrawal of the thin filaments from the A band, as shown diagram-matically in B, 4 and 5 . [Redrawn from Circulation Rev., 15 (Suppl_ 2) : 14, 1964,5 by permission of the AmericanHeart Association .

a load, would be augmented, as would thetnaxitnal pulling force exerted on a fixed stake,as shown here in Panels D and E .

This analogy may prove helpful in an under-standing of the remarkable manner in whichheart muscle is capable of altering its perform-ance . Two fundamental types of adjustmentare possible : (1) changes in the initial fiberlength, i .e., operation of the Frank-Starlingmechanism, which result in an alteration of thenumber of contractile sites brought into playduring the contraction (the number of horseswhich compose the team), and (2) shifts of theforce-velocity curve, which result in reanck men-tal alterations in the rate of force development ateach contractile site (the qualitative nature ofthe horses comprising the team),

CLINICAL APPLICATIONSIt is likely that these basic principles can be

applied to the clinical problem of evaluating, andexpressing in quantitative terms, myocardialcontractility . Figure 7 shows the relation be-tween force, plotted along the horizontal axis,

710

C

t

2

d

FIG . 6 . A simple analogy for two types of shifts of the force-velocity curve . Both theletters and numbers on the pictures at the left can be identified in the force-velocity curves at the right .

and velocity of contractile element shortening,plotted along the vertical axis . 1 ° Each pointwas obtained from a different patient with heartdisease studied by an angiocardiographic methodthat allowed determination of the velocity of

c_,,,an, Vmu .

G

GC

aV 10 ap ybMAVIAWJM LA WALL TENS I-IM/LM,

Fso . 7 . Calculated contractile element velocity (VCE) at thetime ofpeakleft ventricular (LV)wall tension, Measurementswere made angiocardiographieally in normal subjectsand patients with left ventricular dysfunction .

Panel Discussion

n ..s,

LOADee

contractile element shortening and which, to-gether with measurements of intraventricularpressure, made possible the determination ofwall tension . The solid circles represent ob-servations on patients with normal left ventricles,and the triangles, on patients with diseases whichaffect left ventricular function . It is clear thatthe tension developed in both groups was com-parable but that the velocity of fiber shorteningwas markedly reduced in the patients with dis-eases affecting the left ventricle .

In conclusion, it appears that rather simpleprinciples of the physiology of skeletal musclemay provide a useful approach for the measure-ment of myocardial contractility in intact, con-scious patients . These newer technics are based,not upon empiric correlations, but rather on anunderstanding of the ultrastructurc and me-chanochetnistry of cardiac muscle. While itmay be presumptuous, at this point, to claimthat these approaches have already yielded tech-


nics which are easily applicable clinically, itappears realistic to hope that it will be possible,in the not too distant future, to obtain a measure-ment of myocardial contractility and in thismanner to resolve the clinical dilemma so fre-quently faced by the practicing cardiologist .

REFERENCES1 . Hll ., ., A. V. The heat of shortening and the dy-

namic constants of muscle . Proc . Roy . Soc . London .s13, 126 : 136, 1938 .

2 . ABnos-r, B. D. and MOMMAERTS, F . H. M, A studyof inotropic ,mechanisms in the papillary musclepreparation . J, Gen . Physiol., 42 : 533, 1959 .

3 . SONNENBLICi, F. . II . Force-velocity relations inmammalian heart muscle . Am . J . Physiol ., 202 :931, 1962 .

4. SONNENBLICK, E . H . Implications of muscle me-chanics in the heart . Ped . Proc ., 21 (Suppl .) : 975,1962 .

5 . Ross, 1 ., JR ., COVELL, J. W., SONNENBLICK, E . H .and BRAUNWALD, E. Contractile state of the heartcharacterized by force-velocity relations in vari-

Therapeutic Defects of Current Diagnostic Nomenclature*

ALVAN R . FEINSTEIN, M .D .

LMOST 200 years ago, doctors changed the

became pulmonary tuberculosis ; various diarrheasconcepts and nomenclature of disease .

and dysenteries became gastroenteritis and colitis ;Until that time, a patient's disease had been his

and many other clinical titles of disease were con-dis-ease : his symptoms or discomforts . With

verted into the names of anatomic abnormalities .the advent of attention to internal morbid anat-

With subsequent technologic advances of theomy in the late eighteenth and nineteenth cen-

late nineteenth and twentieth centuries, addi-turies, the concepts and names of the dis-ease of

tional types of disease--other than morbidthe bedside were converted to the pathologic

anatomy-were encountered and classified asdisease of the microscope and morgue . A few

entities of microbiology, physiology, biochemis-old "clinical" titles of disease, such as gout and

try and other modalities of the laboratory .rheumatic fever, were preserved . But angina pec-

This current system of diagnostic nomencla-toris became coronary artery disease; consumption

ture, based on the concepts and observations of

* The concepts described here were developed during research supported in part by Grant 0704B67 front the De-partnment of Health, Education, and Welfare, U . S . Public Health Service, Cancer Control Program .



711

ably afterloaded and isovoluu)ic heats . CirculationRes ., 18 : 149, 1966 .

6 . GLICK. G ., SONNENBLICK, E . H. and BRAUNWALU, L .Myocardial force-velocity relations studied in in-tact unanesthetizcd man . .1 . Clip . hoot., 44 : 978,1965 .

7 . Hcxr.BV, A, F. and'PnvLOR, H . K_ Local activationof striated muscle fibers. .1 . Phyriat ., 144 : 426,1958 .

8 licxLEv, Il . E . Structural evidence concerning themechanism of contraction in striated nmscle. In :Muscle, p . 3 . Edited by PAUL, Vr'. M., DANIEL,E, E., KAY, C . M. and MONCKPON, G. London,1965 . Pcrgamon Press .

9 . SPIRO, D . and SONNENBLICK, E. H. A comparisonof the ultrastructural basis of the contractile pro-cess in heart and skeletal muscle . Circulation Res .,15 (Suppl . 2) : 14, 1964 .

10 . GAULT, ,1 . H ., Ross, J ., .IR ., SONNENBLICK, E . H . andBRAUNwALU, E . Characterization of myocardialcontractility in patients with and without cardiacdysfunction by the. instantaneous tension-velocityrelation (Abstr .) . Circulation . 34 (Suppl. 3) :108, 1966 .

Dr. Alvan Feinstein, Associate Professor of Medicine, Yale UniversitySchool of Medicine, has made invaluable contributions to our current con-cepts of the diagnosis and therapy of rheumatic heart disease . In a dis-tinguished series of communications published in the Annals of InternalMedicine, he described with perception and courage the role of the clinicianas an investigator . His interests have included such topics as the teachingof physical diagnosis, the "computer era," and pulmonary carcinoma . Inthese endeavors, as well as in his major contributions to the American Collegeof Cardiology Committee on Standard Terminology, Dr . Feinstein hasdemonstrated a refreshing originality . He will discuss "Therapeutic Defectsof Current Diagnostic Nomenclature ."

712

Fo .o-Cloned

MO PhO/egiC,LotoroIOry

ILLNESS

cr,,,rm l cum .

Sy"pN"s, sgns

FIG . 1 . Types of data as disease and host interact duringillness.

pathology and the laboratory, has helped bringenormous progress to medical science as weidentify different kinds of diseases in our acts ofdiagnostic reasoning . Nevertheless, this patho-logic system of diagnostic nomenclature is alonetoo incomplete and too inadequate for identify-ing the different kinds of patients, rather thandiseases, that we treat in our acts of therapy .

DIAGNOSING AND CLASSIFYING A DISEASE

What happens in nature is shown in Figure 1 .A disease, shown in the large circle on the left,interacts with a host, shown in the large circle onthe right, to form an illness, shown in the overlapof the circles . In working diagnostically at thebedside, clinicians obtain the demographic dataof the host (details of his environmental and per-sonal attributes) and the clinical data of his ill-ness (details of his clinical symptoms and signs) .From these two types of data, we then deducethe name of his disease, and we try to confirmthat diagnosis by demonstrating it with theparaclinical data obtained in various laboratorytests and in morphologic procedures, such asroentgenography and biopsy .

After we establish the diagnosis or name of thedisease, we then treat the patient . If the per-formance of that treatment is to be an act ofreproducible science, we must carefully identifyand correlate both the patient's state before he istreated and his responses to the treatment . Toidentify the patient's state, we must classify hisdistinctions in all three types of data-hisdemographic features as a host, his paraclinicalaspects of disease, and his clinical characteristicsas a diseased host, who is a sick person . All threekinds of data must be classified ; otherwise wecan never be sure that we treat the same kind ofpatient or the same kind of clinical situation .

The main point of my remarks is that many ofour current statistical and clinical controversiesin therapy arise because we do not now have asuitable system of taxonomy for classifying the

Panel Discussion

strictly clinical features of illness that indicate. theeffects and severity of human responses to diseaseand to treatment.

For classifying disease, we have the entirecatalog of modern pathologic and etiologicnomenclature : morphologic entities, such asmyocardial infarction ; biochemical names, such asporphyria; physiologic names, such as ventriculartachycardia ; microbial ones, such as streptococcalinfection ; and the old "clinical" ones, such asgout. For classifying hosts, we have standardcategories to describe such features as age, race,sex and so on . But we have no taxonomy for clin-ical manifestations . All the careful clinical ob-servations that doctors slake of patients and ofhuman illness are not preserved or classified inany organized manner once we diagnose a dis-ease . All of the clinical distinctions are obliter-ated and lost by their conversion into the nameof a diagnosis .

CLINICAL DISTINCTIONS AMONG PATIENTSTREATED FOR SAME DISEASE

Let us consider reports of any treatment thatyou have read about or heard about for patientswith coronary artery disease . In Table I, thereare cited five different kinds of clinical featuresthat distinguish one type of coronary patientfrom another . As you read them, I invite youto try to recall whether you have ever seen anyreports of therapy in which the patients werespecifically identified in groups, according tothese distinctions, and whether the results oftherapy were noted for these different categoriesof patients . The first clinical feature is mode ofdetection. Did the patient come to us because hehad symptoms, or was he asymptomatic and ac-cidentally found to have coronary disease dem-onstrated in a routine electrocardiogram? Thesecond feature is his cluster of clinical manifesta-tions . Did he have primary clinical featuresonly (such as chest pain), or only the complica-tions or secondary clinical features (such as con-

TABLE IClinical Distinctions Among Patients with the Same

Diagnosed "Disease"

1 . Mode of Detection : symptomatic or asymptomatic2. Cluster: presence or absence ofprimary and secondary

clinical manifestations, alone or in combination3 . Sequence : order in which the manifestations occurred4. Timing: duration of individual or collective mani-

festations5. Co-morbidity : coexisting diseases or other clinical states

THE AMERICAN JOURNAL . OF CARDIOLOGY

gestive heart failure and arrhythrrtias) or did hehave both primary and secondary features''1' he third point is his sequence of manifestations .Did he have angina first and then later conges-tive heart failure, or congestive failure and thenangina? The fourth is timing . Had he beenhaving angina for 12 years or for 12 days? Thefifth is co-morbidity. Was he otherwise healthyexcept for his coronary disease, or did he havesome additional disease such as diabetes mellitus,hypertension, or cancer?

All of these clinical features are things thatevery clinician constantly thinks about in plan-ning treatment and in evaluating results of treat-ment . Yet these features, which you wouldwant to know about to decide whether someother malts work is applicable to your patient,are seldom, if ever, specifically cited, correlated,tabulated and analyzed in the so-called scientificpresentations and reports of treatment . Whyriot? Because there are no formal categories forthem . I suspect that until I just called thesefive features to your attention, many of youwould not have thought of labeling them thatway ; and I suspect that such terms as cluster,sequence, and co-morbidity are new to you-at leastthe way they are used in this context . Yetevery one of these concepts is perfectly familiarto you . Every clinician constantly thinks aboutthem whenever he evaluates and treats a patient .But the concepts are omitted when clinicians andstatisticians engage in what is called a scientificanalysis of therapy .

In the absence of such labels and categories toidentify comparable illness or comparable "lit-ter-mates" of human disease-in the absence ofsuch a clinical taxonomy for classifying sickpeople neither clinicians nor statisticians canadequately specify the contents of the popula-tions exposed to therapy . The statistician usuallyarranges all the information according to thedemographic, paraclinical and diagnostic cate-gories that he has been taught to use, but liegenerally omits any categories that represent thedistinct features of clinical details and clinicalseverity in illness . The consequence of theseomissions is the chaos of statistics in moderntreatment, a chaos not just in treatment ofcoronary artery disease, but in cancers, hyper-tension, diabetes mellitus, emphysema and allother major chronic ailments of people . Thecritical clinical distinctions of patients arcomitted because we do not have an appropriateclinical taxonomy as part of our diagnosticnomenclature.



I'AISLE IIntellectual Maladies in Clinicostatktied

Reports of Therapy

713

1 . Absenec of standard clinical diagnostic criteria formost diseases

2. Problems of observer variability3 . The fetish of randomization, with neglect of clinical

comparability4. The worship of a measured distension, no matter how

inappropriate to the problem5 . Absence of specifically stated objectives and criteria

fur therapeutic accomplishment

OTHER DEFECTS IN STATISTICAL REPORTS OFCLINICAL THERAPY

Having pointed out those sources of difficulty,let me note, in Table u, a few other intellectualmaladies in statistical reports of clinical therapy .The first is the absence of standard clinical diag-nostic criteria for most diseases that must beidentified during life . For example, more thanhalf of the authors who present reports of treat-ment do not cite the specific clinical, electro-cardiographic, laboratory, or other evidencethat they use for such diagnoses as coronary arterydisease, ischemie heart disease, myocardial infarctionand impending myocardial infarction .The second is the problem of observer vari-

ability . All of our clinical data, as well as all ofour data in radiography, histology, cytology andelectrocardiography depend on opinions and in-terpretations of human observers . Yet only iuthe past decade have we begun to do studies ofthe variability among those human observers,and to attempt to improve their consistency andstandardization .

The third is the statistician's fetish for ran-domization . Randomization is an importantand valuable procedure, pro ided the comparedpatients are first made clinically comparable .If the statistician omits this initial effort toachieve clinical comparability--and he usuallydoes omit it-randomization can be a source ofdelusion, deception and disorganized chaos .

The fourth is the worship of a measured nun,-her, no matter how inappropriate to the prob-lem. Thus, although we may want to know intreatment whether a patient still has pain, orwhether he can walk or work, the published re-port tells us instead about a change in the firstderivative of a graphic curve, or that his serumlicorice level has dropped 10 points .

The fifth is the absence of specific objectivesand criteria in reports of therapeutic accomplish-

714

ment. For example, most authors fail to indi-cate specific evidence and criteria for the judg-ments they make when they use such terms asindicated, contraindicated, better, worse, improving, orrelapsing . In the literature on anticoagulants incoronary artery disease, authors commonly talkabout preventing thromboembolic phenomena, butseldom indicate the clinical and other observa-tional criteria that they used to identify athromboembolic phenomenon .

CONCLUSION

Modern technology has given clinicians amagnificent series of adjuncts for establishingdiagnoses of disease but has also provided phar-macologic and surgical advances that maketreatment far more effective and dangerous thanever before. When we work as clinicians today,our main scientific challenge is how and when touse the potent therapeutic maneuvers at ourdisposal. We cannot solve that challenge

THE advances in cardiovascular surgery inour lifetime have been electrifying . The

American College of Cardiology has acknowl-edged this by the election to its Presidency of C .Walton Lillehei, one in the forefront of the smallgroup who in the early 1950's established thefeasibility of open heart surgery using cardiopul-monary bypass . As we look back upon the de-velopment of cardiovascular surgery-back tothe first successful pericardectomy, the first suc-cessful closure of a patent ductus arteriosus byGross, and through the development of closed

Panel Discussion

merely by studying the diagnostic nomenclatureof pathology, the numcrologic theories of statis-tics, the chemical formulas of pharmacology, orthe dehumanized abstractions of molecularbiology . We need more basic research in clini-cal medicine today, but the research should in-clude fundamental problems in the science thatis basic to clinical therapy; this "basic science"is not an esoteric domain of the laboratory but isthe careful clinical observation and classificationof sick people . It is time that clinicians onceagain began to respect the scientific importanceof their own intellects and observations . Theclinician is the apparatus that plans and deliverstherapy, and it is that apparatus and the patienthe treats that need more scientific attentiontoday-not merely because such attention isproper, decent, humane, traditional or senti-mental, but also because a better knowledge ofclinical and human distinctions is the basic pre-requisite of science in medical treatment .

Some months ago I discussed the concept of this symposium with a numberof panelists participating today . They said that there was a nationallyrecognized individual who would be indispensible for such a format sincehe has demonstrated rare talent in understanding trends in cardiovasculardisease and has manifested the courage to speak out when, in his opinion,certain practices were ill-conceived . In the opinion of his peers, a sym-posium devoted to creative, provocative and imaginative concepts wouldbe incomplete without Dr . Kirklin . Dr. John Kirklin is Professor and Chair-man of the Department of Surgery, University of Alabama Medical Center,Birmingham, Alabama .

Obstacles to Proper Understanding of Surgery

for Heart Disease

JOHN W. KIRKLIN, M.D ., F .A.C.C .

mitral commissurotomy by Bailey and Harkenand the invention of prosthetic valves-can weidentify some reasons why our knowledge andtechnics are still somewhat imperfect? I thinkso .

First, of course, it could be argued that knowl-edge and technic are really not so imperfect . Iwould agree that operative mortalities for manycomplex intracardiac operations are less than 5per cent and that long term results are in manycases superb . But small infants with certaintypes of lesions still present a difficult problem,


and adults in chronic congestive heart failurefrom valvular heart disease do not always getthe kind of result that is desired . Some predic-tions for future accomplishments are beingmade on the basis of hope rather than knowl-edge . Some explanations for the persisting im-perfections in our care of patients can be found inthe bias of surgeons, sortie in the bias of cliniciansand some in gaps in our knowledge . Perhapsall these are related .

Some of the factors contributing most impor-tantly to the success of surgeons in treating heartdisease have implicit in them some impairmentof progress . Enthusiasm, an important ingredi-ent of success, can lead subtly and easily to lossof self-criticism and incomplete reporting of un-favorable aspects of a new field . Dedicationand hard work can result in loss of perspectiveand initiative . Success in a high percentage ofclinical cases can lead to overconfidence in theperfection of one's method and may make onetoo tolerant of his occasional failures and toowilling to rationalize then, rather than to seektheir true explanation . Enthusiasm, dedica-tion . hard work and success are highly desirable,but by recognizing the traps they bait for us wemight be able to increase our knowledge and oureffectiveness in treating heart disease even morerapidly .

CARDIOPULMONARY BYPASS

The advent of successful cardiopulmonarybypass and open cardiotomy quite properly gen-erated excitement in the surgical world in themid-1950's and led to effective operative treat-ment of many types of congenital and acquiredheart disease . Soon, however, extravagantclaims were made of the advantages of some ofthe pump-oxygenator systems that were devel-oped . It is now apparent that each of theseveral basic types of pump-oxygenator systemshas certain advantages, and these have beenemphasized extensively . However, the disad-vantages of the systems, individually and gen-erally, have not been so widely presented .

One of the first clear statements of one of thesewas a paper presented several years ago byMaloney, Lees and colleagues concerning pro-tein denaturation in pump-oxygenator systems .Physical chcn .ists knew that this must occurwhen blood passes through a pump-oxygenator,but Maloney and associates demonstrated itsexistence in these systems, demonstrated that itoccurred in greater magnitude in sortie types ofsystems than in others, and brought these facts to

VOLUME 20, NOVEMBI 4 1907

Stimulations and Provocations 715

the attention of cardiovascular surgeons . Sub-sequently a few significant studies have beenmade of the unphysiologic characteristics ofcardiopulmonary bypass as it is now performed .A group of investigators at the MassachusettsInstitute of Technology, arid others, have en-gaged in studies of the effects of mere contact byblood on certain materials used in pump-oxygenators. Bernstein and associates at theUniversity of Minnesota have made sophisti-cated studies of red cell destruction duringpumping . Our studies have shown that oxygenconsumption gradually falls during cardiopul-monary bypass, suggesting that less and less ofthe uricrocirculation is perfused as bypass con-tinues. This may be related to the essentiallynonpulsatile flow that exists during cardiopul-monary bypass . Many additional studies needto be made of the physicochemical imperfectionsinherent in our present systems for cardiopulmo-nary bypass, and of the ideal method for arterialinput to the patient .

ASSESSING RISKS OF SURGERY

Cardiologists and pediatric cardiologists havecontributed greatly to the development of cardio-vascular surgery, but they too have sometimesdelayed progress . There seems always to developa reaction against every action, and in the cardio-vascular world one manifestation of this hasbeen development of the concept that some veryserious forms of heart disease may not be sohazardous as is surgical treatment . It is a littleamusing that in the 50 years prior to the develop-ment of open intracardiac surgery there waslittle activity on the part of the medical world instudying precisely the life history of congenitaland acquired heart disease. In one's moremorbid moments, he wonders what cardiologistsand pediatric cardiologists did in all the yearsbefore they adopted the role of protector of thepatient from the surgeon . They should havehad several lifetimes to investigate the life his-tory of various forms of heart disease, an activitywhich only lately has come to interest them . Inassessing the relative risks of surgery and of thedisease itself, they are prone to use the early re-sults of surgery for comparison rather than morerecent ones which have been improved by thesebitter earlier failures . They have sometimesgeneralized unfairly and improperly concerningthe shortcomings of certain intracardiac opera-tions just because they didn't happen to be welldone in their own institution . Of course, sur-geons have not always been as objective as they

716

Panel Discussion

should have been and, as already indicated, haveat times been overenthusiastic . But I truly be-lieve that surgeons are encouraged to be objec-tive and orderly in their progress when theirmedical colleagues are basically sympathetic andprogressive . Unwarranted conservatism andbelittling criticism of surgeons can only provokethem into foolish aggression, and help neitherthe patient nor science .

MITRAL VALVE SURGERY

And yet we must admit that at tithes surgeonshave generalized beyond their data in certainareas and have minimized the complexities ofthe problem in other areas . The developmentof surgery for acquired mitral valvular disease isan example . With nearly each change in thetechnic of opening the stenotic mitral valve, theprediction has been made that the incidence ofmitral restenosis would thereby be significantlyreduced. The accumulated data now indicatethat mitral restenosis results primarily fromnatural progression of the inflammatory andfibrotic process in the mitral valvular apparatusmaking the leaflets stiffer, more calcified and lessable to open and close properly as time passes .This occurs in approximately the salve inci-deuce, no matter how the valve has beenopened . It is important to emphasize that thevalve must be opened . In earlier days the cout-missures were not opened properly, and therewas often persistent mitral stenosis, a problemthat is related to the type of operative procedure .

Because of the problems associated with thedevelopment of the operation of mitral commis-surotomy, a few surgeons have advocated rou-tine replacement of the mitral valve in patientswith mitral stenosis. This must certainly beunwise in the present state of our knowledge .In properly selected patients, namely, thosewhose mitral valves arc pliable, competent andstenotic, closed conunissurotomy employing thetransventricular dilator can be done at a lowoperative risk and with significant relief of symp-toms for a long period in most patients . Theneed for an open operation and mitral valvularreplacement can then be deferred indefinitely insome patients and for many years in mostpatients .

Yet as we defer valvular replacement in somepatients, we must be cognizant of the disadvan-tages always inherent in deferring correction ofacquired mitral and aortic valvular heart dis-ease . As the patient continues through the lifehistory of his disease, there develops at some

point in time impairment of left ventricular con-tractility and efficiency . The reduction incardiac output, severe exercise intolerance andchronic congestive heart failure are usually re-lated not only to the valvular lesion but to reduc-tion in left ventricular function as well . Wehave some evidence that the cardiac output islowest early postoperatively in patients with lowcardiac output and impaired ventricular func-tion preoperatively . Clearly then operativemortality rates are going to he highest in pa-tients with long-standing heart disease and un-paired ventricular performance . Further, it isknown that after successful replacement of themitral valve some patients, although improved,do not regain the ability significantly to increasecardiac output with exercise and continue tohave some symptoms . This all suggests thepossibility that established impairment of leftventricular function and efficiency may not in allpatients return postoperatively to normal func-tion and efficiency . This is such an importantgap in our knowledge that in our institution,with the cooperation of Drs. Dodge and Reeves inthe Department of Medicine, we have initiated along term study of the reversibility by surgery ofestablished impairment of left ventricular func-tion and efficiency and of left ventricular hyper-trophy. If lack of reversal occurs in a significantnumber of patients, it will indicate the need forearlier operation once the thrombocmbolic com-plications of valvular replacement have beenminimized .

CLINICAL CONGESTIVE HEART FAILURE

An obstacle to universally good results aftervalvular replacement is the fact that an occa-sional patient continues to exhibit the syndromeof chronic congestive heart failure months afteroperation . They have fluid retention, hepato-inegaly and elevated jugulated venous pressure .It is tempting to believe that unrelieved tricuspidvalvular incompetence is etiologic when thissyndrome persists postoperatively, but a numberof cases have been seen in which there was noevidence of this . These simple facts make itmandatory that we understand the pathophysi-ology of chronic congestive heart failure and itsinfluence upon the body composition of the pa-tient in the early days after operation and in themonths that follow . As we study this, our atten-tion must also encompass the relations betweentotal body water, interstitial fluid, plasma vol-mile and blood volume . Also the distributionof blood volume between the central and periph-

TIIE AMERICAN JOURNAL OF CARDIOLOGY

oral vinous and arterial systems is an importantarea of investigation, since it provides a part ofthe expla nation toe the very high left atrial pres-sures sometimes seen early postoperatively .

Sonic things, of course, are known at present .The Untreated patient with chronic congestiveheart failure has abnormally large volumes oftotal body water, extracellular fluid, interstitialfluid, plasma and red cells . Total exchangeablesodium is increased, and exchangeable potas-siuut decreased along with a reduction in bodycell mass. The studies of Braunwald and col-leagues have quantitated the impaired ability toexcrete an exogenous sodium load in the urineexisting in these patients. With intensive medi-cal treatment total body water, total extra-cellular fluid, interstitial fluid, plasma volumeand exchangeable sodium decrease strikingly .Red cell mass, exchangeable potassium andbody cell mass change little, and the tendency ofthese patients to develop cachexia is not con-trolled by digitalis and diuretics . Successfuloperation does result, in many patients, in disap-pearance of cachexia, increase in body cell mass,and restoration of body composition to normal .The results in such patients are dramatic andgratifying, but the few who, as mentioned, fail tobe relieved of chronic congestive heart failurepose a serious problem .

It is not known whether the failure is due pri-marily to a persistence of the impairment of theprerenal and renal mechanisms for excreting


Stimulations and Provocations 17

sodium in spite of an improvement in cardiacperformance, or whether the phenomenon is dueto persisting impairment of cardiac performanceand only secondarily of the ability to excretesodium . Methods are available to us for inves-tigation of this problem, and appropriate an-swers should be forthcoming . The knowledgewill be important to future decisions relevant tothe proper timing of operative intervention inthe individual patient .

CONCLUSION

I have today made some complaints againstmy surgical colleagues and myself for our in-adequacies . I have voiced criticism of certainviews and attitudes of our medical colleagues .Yet I am, of course, proud of the knowledge thathas been gained, proud of the unique collabora-tion that has existed for the most part betweensurgeons, cardiologists, pediatric cardiologists,physiologists and others in the creation of thisnew field of endeavor. Perhaps, most of all, Iam anxious that we continue to investigate andthat we not become vain as we view our progress .I am anxious that we not extrapolate too farbeyond our present state, that we not promise toourselves and to the public the achievement ofgoals that are not at this moment realistic . Ourtrue progress must continue to be based on re-search done painstakingly and accurately and onexperience honestly reported and wisely in-terpreted.

Documents

Stimulations, provocations and new frontiers