Download SYMPOSIUM ON CONGESTIVE HEART FAILURE

SYMPOSIUM ON CONGESTIVE HEART FAILURE
Hemodynamic Aspects of Congestive Heart Failure
By
L.
N. KATZ, M.D., H. FEINBERG, PH.D.,
AND
A. B. SHAFFER, M.D.
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The 3 articles in this issue on congestive heart failure comprise the first of 10 contributions on this subject. The remaining 7 articles will be published in the February and
March issues.-EDITOR.
IN this discussion of the hemodynamic aspects of congestive heart failure, we propose to review clinical observations and the
results of animal experiments. On this basis,
our concepts concerning the sequence of
changes in the heart that lead to congestive
heart failure are summarized.
It is well known that congestive heart failure, while starting as a deficit of myocardial
performance, ends as a syndrome in which
many organs, particularly the kidney, lungs,
and liver, are altered, as are many homeostatic functions. Certain aspects of this subject have been considered in previous reviews,1-9 or are dealt with in other sections of
this symposium. In the present review, we
will confine ourselves primarily to the heart,
and especially to those of its alterations, physical or chemical, that are recognized as having some possible bearing on the disturbed
hemodynamics of congestive heart failure.
Congestive Heart Failure Defined
The function of the heart is to eject the
blood that is returned to it. It is obvious, then,
that the heart is as much the servant of the
circulation as its master. It is often difficult
or impossible, in man, to separate clearly the
primary hemodynamic manifestations of a diseased heart muscle from those of a primarily
compromised circulation, or from secondary
circulatory adjustments.
An inadequate circulation (circulatory insufficiency or failure) is manifest by a low
cardiac output in relation to the current needs
of the body, or by the accumulation of undue
quantities of blood in the systemic or pulmonary venous system, or both (congestive circulatory failure). On the other hand, the
term heart failure in this report is considered to be synonymous with myocardial failure, which implies as its starting point an
inadequate myocardial contraction with reference to the circulatory load. It should be
clearly recognized that there are many extracardiac causes of circulatory failure and that
myocardial failure is only one of the cardiac
abnormalities, structural or functional, which
may result in circulatory failure.
Just as miyocardial failure is niot a necessary condition of circulatory failure, so the
absence of circulatory failure is no guarantee
of an uncompromised myocardium. A normal
circulation may be maintained by an augmented cardiac effort, with a resulting decrease in cardiac reserve.
Myocardial effort is directed toward meeting 2 types of load. The heart must accelerate
From the Cardiovascular Departmient, Medical Research Institute, Michael Reese Hospital and Medical
Center, Chicago, Ill.
The studies of the department in this area have
beep supported recently by the American Heart
Association, National Heart Institute, and the
Michael Reese Research Foundation, among others.
Dr. Feinberg is an Advanced Researeh Fellow,
American Heart Association.
Circulation, Volume XXI, January 1960
95
96
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the m-lovement of the blood returninig to it (iniput or diastolic load) anid must, at the same
time, overcome the resistanee to its ejection
(resistance or systolic load). The normal myocardium responds to ani incereased load in a
variety of ways, depending onl the type of
load, its magnitude ancd its rate of development. Tachyeardia and dilatation represenit
the more acute, ''crude ' adjustients to an
inereased load. Dilatationi is also a conisequence of chroniieally iniereased diastolic load.
Hypertrophy, oni the other hanid, represents
a more gradual respon-se, and is most imarked
in instanees of chronieallv increased svstolic
load. More subtle are the processes witlhin the
heart musele itself, for the most part neurogenieally or hormonially conditioned, which
determninie the behavior of the miyocardium
fronm beat to beat (see below).
"Myocardial reserve"' relates cardiac effort, however measured, to the maximnumn effort of which the heart is capable with respe(ct to the particular aspect conisidered.
Increased work loads obviously niarrow the
gap betweeni existing an-d maximal efforts,
while myocardial disease narrows the gap by
reducing the possible effort maximlum. The
concept of cardiac reserve has limited usefulness clinically, bowever. since it encomlpasses
so mlany faetors anid there is lno standard wa;y
of applying it. For example, hypertrophy of a
venitricle iiicrea;.es cardiae reserve in one senise,
but reduces it in another, since as hypertrophy develops, there is less potenitial for
further hypertrophy.
The followinig incomplete tabulation serves
to illustrate by means of clinieal examples
the relationship of (ircu-tlatory to mvocardial
failure. Circulatorv failure resLults froml
1. Initerferenee with systemnice venouLs retuirn
(lne to factors remote fro-n the heart (sueh
as hemorrhage, peripheral vascular collapse.
shock), or ini the heart region (such as peri( ardial tamponade, (onistrictive pericarditis
tricuspid stenosis). Congestion is generally a
feature of the latter group but niot of the
forimer. Mvocardial failure is not a nlecessary
concoinitant of these states.
KATZ, FEINBERG, SHAFFEIR
2. Interference with the ptluiping or filling
mechaniies of the ventricles due to som:ie arc-hitectural abnormality. This need lnot be associated initially with m-ocardial failure (viz..
acute pulnioliary edemua dlue to mitral stelnosis), but ultinmately leads to circulatory failuire oni the basis of failure of olne or both
Avenitrieles (e.g.. semiluniar valvular stelnosis
or inisufficiellcy, mnitral stenosis or insufficiencvy,
tr ic-uspid insufficieniey, arterial hvpertenssioi
of either eireuit, pulmiioniary ei-umboli or thrombosis). In all these conditions, forward flow
through the arteries, though initially niormal,
is sinall in rielationi to the amount of effort that
the heart must exert.
3. Primary diseases of the iivocardiumiii that
lead to muscle failure. These meay be due to
localized loss of substance (as in mnvocardial
inifaret), or to diffuse involvemlenit (as in mnvocarditis, amyloidosis).
4. Any stimulus to high output of onie or
both ventricles, be it hvpervoleniiia (as ini excessive intraveenous infnSioii of bloodl or other
fluid, an(d possibly acute glomerulonephritis),
drastic reduetioln in peripheral vascular resistance (as in systemic A-V fistula, beriberi.
hyperthyroidism, Paget 's disease), hypoxia
(as in aniermiia, chrommie cor pulmonale) or
possibly a direct metabolic effect oni the IyVocardiumi (as might occur in hyperthyroidisnm).
Also ineluded in this group are uncomplicated conlgenital cardiovascular mualformlations with large left-to-right shunts. In these
(onditions, systemic flow m-ay be reduced
while pulmomiary flow is inereased, and the
diastolic load to one or the other ventricle is
miiarkedly iniereased (the right ventricle i
imiteratrial septal defect, the left venitr-icle it:
patent duetus arteriosus). With the exceptionof the last-menitionied conditions, the obviouis
lhemodvynamiie miianifestationis of "'high ouitput cir(-llatory failure are bx- definition (i0o1gestive onily, at least initially. However, the
presencee of a high cardiae output must nlot
be takenm to inmply that flow to all orgains, e.g.,
the kidnevs. is necessarily high, or eveln miorna]. The ciontroversv con-tinues as to whether
nvocardial failure per se :ini man miax- occur
Circulation, Volume XXI, January 1.960
SYMPOSIUM ON CONGESTIVE HEART FAIILURE
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simply on the basis of an " overwhelming"
diastolic load. Certainly some of the conditions leading to high output circulatory failure have an additional primary deleterious
effect on the myocardium itself (as in the
hypoxic group, beriberi, and possibly in acute
glonmeruloinephritis and hyperthyroidism),
and then myocardial failure may be precipitated much as it may be under the stimulus to
high output of physical exercise. In other inistances (as in "iatrogenic" hypervolemia, arteriovenous fistula, "malignanti" ductus arteriosus), the only effect of the underlying
process on the myocardium is hemodynamie,
and it would seem unlikely in such instances
that there must invariably be a separate myocardial disease. Thus, it is by no means ruled
out that these "high output states" can lead
to congestive heart failure, as defined, insofar
as they may give rise to a diastolic load with
which even a normal ventriele cannot cope.
Here congestion may be in part the cause anid
in part the result of myocardial failure.
It is obvious that in a given elinical condition, the causes of circulatory failure may be
multiple. Further, compensatory mechainisms
within the heart itself (such as inapparent
dilatationi) or at the periphery (such as
slightly inereased oxygen extraction) may
prevent myocardial failure from being mainifest in its earliest stages.
A given entity may not fit into a single
group. For example, the behavior of endocardial fibroelastosis in a given ease may
classify it in any of the first 3 groups. Functional derangements of the heart or eirculatioln (vaso-vagal syncope, rapid heart action,
cardiac arrest) also may result in circulatory
failure in the absence of myocardial failure.
These groups constitute a crude therapeutic
classification. There is no doubt that the best
treatment of any hemodynamic abnormality is
a direct attack on the primary cause. This is
the only effective approach to the conditions
in group 1, while measures (such as digitalis)
aimed at supporting the compromised myoeardium mnay be very effective in groups 2
and 3. The clinical response to such measures
Circulation, Volume XXI, January 1960
97
is characteristieally erratic in the heterogeneous group 4.
Congestive Heart Failure in Man
Considerable knowledge concerning the
heart and eirculation in health and disease has
been obtained through the use of lnewer technies such as cardiac catheterization. It is, of
course, not possible to explore the human
heart with the same precision, under stable
conditions, or with the opportunity to alter
these conditions, as is the case in animal experiments. Sometimes the imperfections and
limitations of the methods employed in manl
have been ignored or minimized in attempts
to evaluate the basic importance of the findinogs. While there is little reason to doubt the
validity of muost observations, their iniplicatious are linmited with regard to basic understanding of myocardial function in health and
disease because of the inadequate methodology.
On the othier hand, such studies have to somen
extent indicated the niecessary direction of
more basic work.
Cardiac catheterization of the right side of
the heart, anid, to a lesser extent, of the left,
has contributed to knowledge in this field inisofar as it has made possible the adequate measurement of pressures anid mnean flows in the
cardiovascular system of normal individuals
alnd patients in heart failure. Such measurements have been made with the subject at
rest, on exercise, under the influence of certain drugs (e.g., epinephrine), and during certain other procedures such as rapid intravenous infusion or venesection. Many of these
studies have been attemnpts to inivestigate the
validity of Starling's law in the intact human
being.
Hemodynamic studies of normal individuals
at rest and exerciset0-12 have indicated the
normal ranige of nminute and average stroke
outputs and the expected low levels of right
and left -ventricular diastolic pressures (the
latter measured via the pulmnonary arterial
wedge). There has been, in general, no consistent relationship betweein ventricular diastolic pressure changes and alterations in
stroke volume, heart rate, minute output, or
98
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externial work (per mL-inute or per beat).* Onie
studv, iii which iiitrathoracie pressure was
mteasured, thus allowing determination of true
right ventricular diastolic pressure, demonistrated a direct relationiship between this press-uire, as a measure of right vTentricular filling
pressure, and cardiac output as an index of
in:vocardial effort.14 The effects of rapid initravenous infusion- or venesection on the relation-ship of ventricular diastolic or atrial pressure to cardiac output or external work have
not been eonisistenit from study to study.'1 i-S
Epilnephrine, however, was shown, many years
ago, to alter cardiac ouitpUt inldependenitly of
right atrial pressure.' "
The mnore gross henlodyvanamie aspects of congestive heart failure, as in groups 2 anid 3
above, have also been revealed by catheterization. The measurable hemuodynamic expressions of poor inyocardial contraetility are essentiall-y those of eirculatory inisufficieiiev, i.e.,
high venitricular diastolic pressure (mongestion
with the cause localized to one or both yventricles) anid diminiished cardiac output. On
exercise, diastolic pressure rises further while
miiiute output (as mneasuired) mnay rise slightly,
remain stationrary, or eveii fall.1' 20 Of course,
(irculatorv insuffieiency, not demonstrable at
rest, ima- becomie apparenit o01 exercise. When
cardiae outpult is detei iniiied by the Fick priiciple, inadequacy in congestive heart failure is
haracterized by a large A-V oxygen- differecice relative to the level of oxygen coinsumptioii, in.Lidatimog that the tissues comnpensate
for the reduced rate of flow by greater oxygen
extraction per unit of available blood. Low
cardiac oultput may also be a feature of myxedema, but here oxygen consumption is often
low a(ld the A-V oxygen differenee at rest anid
exercise is aot relatively widened,21 22 indi(ating that flowJ reinain.s proportionial to the
oxygeni demnands of the body.
*The classical parameters of external wvork are
minute eardiac output and blood pressure in the
great vessel leaving the ventriele under study.
Stroke work (average) is externial wvork per iminlute
(livided by heart rate. The ivork donie ii imparfting
kinietic eniergy to the ejeeted biloodl is usually nteg-
leeted.'3
8KATZ, FEINBERG. SILAFFERl
Suclh studies ha-ve also r evealed that venitricular end-diastolic pressures well above the
niormal ralnge mlay be associated with mnarked
ventricular hypertrophy (as in aortic or pulmuonie stetnosis) in the absencee of other evideuce of heart failure.23, 24 It is postulated
that this is due to marked thickening of the
ventricular wall which has altered the distenisibilitv of the relaxed clhamber.
Circulatory alterationis caused by rapidly
acting digitalis preparations have been studied
in cases of congestive heart failure. In general,
right (aand indirectly determiiied left) ventricular diastolic pressure falls (reducing coligYestioii) while eardiae o-utput rises and the
heart rate (inconstantly) slows. There is, however, no tinaiiiinity amoiig the various observers about the order in which these changes
oecur. Sometiines, there hals beeii a fall in veiious pressure followed bv a rise in cardiac outl)ut2) suggestiui aii effect of digitalis oii the
venous system siiiilar to venesection?, leading
to a fall in pressure and veenous retuLrn so as
to "'decomtpress'' an- ineompetent venitriele.26
Ini other instances, cardiac output rises without
hiaioge iii venous pressure, or with a subse(lueit fall in this pressure 27, 28 ii-dicatini the
more accepted mvocardial effect of digitalis.
Venotis pressure :mav also fall without a rise
ini cardiae output.") The heart rate mnay be
slowed as a primary -ffect of digitalis (particularly iii atrial fibrillation ), or slowing may
reflect imiiprovemeent in the myvocardiuimn.
I-icreased eardiac output with or without
iciereased venitricular diastolic pressures (direetly or inidirectly nmeasured) has beeni denioisti,ated in many of the "'high output''
states.Y0 Ini contrast to groups 2 and 3, high
Avenous or atrial pressuires, when preselit, are
imot characteristically altered by digitalizatiols.< Ini onle study, digitalis was fouind to
have anl effect in patieints with large (apparentlv dilated) hearts who were clinically not
in failure, similar to its action on the normnal
heart.39
Ini brief, then, while low cardiac output,
dilated ven tricular chamibers, anid high ventri(ular diastolic pressures, collectivelv
Circulation, Volume XXI, January 196f0
SYMPOSlUMl ON CONGESTIVE IIEART FAILURE
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characterize myocardial failure, each can exist
alone under conditions in which myocardial
failure is apparently absent.
Such observations are valuable but present
a very incomplete picture. There is the difficulty of assessing the alteratiolns in cardiovascular pressures against the background of
respiratory variations in intrathoracie pressure. Further, the observations are onily spot
samples in a long drawln-out process, as obtained in the closed circulation of an intact
human being. Again, the possible beat-to-beat
changes in stroke volume and the possible
changes in stroke volume of one ventricle
inidependenitlv of the other cannot be detected
in nman. Consequently, it has, for example, so
far been impossible to record directly the
imomientary disparity in output between th6 2
venitrieles that is presumed to play a part in
the development of pulmonary congestion in
left ventriclar failure, or to lead to its relief
oii treatment.
Basic to a full uniderstaniding of the behavior of the iiormal or failing heart as a
pump, is knowledge of (1) the indices of myocardial performance or effort, (2) the factors
influencilng myocardial effort, and (3) the
energy cost of such effort. As mentioned,
clinical work directed to these imatters has
been dominated by the concept that relates
cardiac effort to venitricular end-diastolic voliine, as enunieiated by Starling and his followers. Thus, external work, per minute or
average per stroke, has so far been the only
index of myocardial performance measurable
in maln. As detailed below, there are strong
theoretical objections to its use as such. So
far as factors influencing myocardial effort
are concerned, venitricuilar end-diastolic pressure is a highly questionable index of enddiastolic volunme. Attempts have been made to
determine en-d-diastolic volume in man
through the determilnation of residual volume
by radiologic40 or dye-dilutioni technics4'
(enid-diastolic volulime = residual volume +
stroke volume), buLt these are difficult to apply
anid again would yield average values. The
clinical observationl that the normal human
Circulation, Volume XXI, January 1960
99f
heart decreases in size radiologically upon
chaiige froin supine to erect position, anid at
the comnmeneement of physical exercise,40 casts
doubt on end-diastolic volume as the only, or
even the imost imnportanit, influenice oni myocardial effort.
W\ith reference to the third point, mneasurements of cardiac oxygen consumnption in nman
have been based oni measuremenits of flow in
the coronary Sillus and its oxygen content.42
However, the corolnary sinlus flow is not a certain measure of total coronary flow,43 44 nor
does it necessarily indicate the mural flow in
the left ventricle or ainy fixed portion of it in
com-iparisonis of a group of individuals.45 Inl
fact, recently the septal branch of the left
descending corolnary artery in the dog has
been shown to drain principally via Tliebesiain
chainnels.46 Even- in the samue persoii, the
drainage area of the coron-ary silnus may shift
wheni the state of the individual is altered by
drug or other procedure.47 There is sufficient
uncertainty, therefore, in this method to lead
onie to demand qualified evaluation of the data
obtained when it is at variance with aniimal
studies in which coroniarv flow measurements
are nmore precise. This is further niecessitated
by the well-knowni fact that the coroniary sinus
blood does niot represent aln exact nor constant in-dex of total coronary venious blood
oxygen (or substrate) colntent.
The data based on the coronary sinus
method are, however, the best so far available
in man. These indicate a correlatioim between
external work of the heart and mvyocardial
oxygen consumption.49 It is also reported that
the mllyocardial oxygen consumption of the
area drainied bv the coronary siinlus is lornoral
in the preseniee of congestive heart failure.50
Also, it rises oii exercise as in the niornmal,49
and is unaffected by digitalis.50 The increase
in mvyocardial oxygen consumption in the
nornial individual on exercise has been attributed to adjustmiients according to Starhiuog's law.49 This is openi to question because,
amtonog other reasons, nio mneasuremnents of enid-
diastolic volumle were mtiade. But miiore signiificanit reasoiis for douLbt are the newer coin-
i()O
cepts of the perfoirmiance of the heart that
lhave recenitly arisen- as a result of animial
studies. They have been summarized, elsewhere6-' -nd are discussed below as they relate to the development of a basic understanidinig of heart failure.
Mechanisms Involved in Experimental Cardiac
Failure
Steps Involved in Muscle Contraction
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Obviously congestive heart failure as defined must ultimately be referred to incomp)etence of the eardiae mnusele, either as a
p)rimary event or secondary to an excessive
load. We aire eon.cerned with the funLdamnelntal
niature of the mvocardial inlcomupeteniee. Since
eniergyv is necessary for this perfornmaniee of
work, cardiac miusele energetics (metabolic
sources of eniergy for myoeardial contraction
and its conversion to mnechanical energy) is a
good starting point for a svstematic discussion
of this natter. The termninology of Wollenberger is useful in this connection.51 Energy
liberation is defiled as the process conceerned
with the supply of energy and includes both
the enzymuatic oxidationi of substrates, such as
glucose, lactate, and the coupled tranisfer of
eniergy derived fromn oxidative processes to
the so-called high-energy coimpounds such as
adenosinetriphosphate, adenosinediph osphate,
creatin-e phosphate-the process of oxidative
phosphorylation. Energv uttilization, on the
other hancd, is defined as the process cooncerned
with the expenditure of the liberated and
stored energy in the developinent of contractile tensioni and heat. In the strict sense, therefore energy utilization is chemieal-inechanical
couplinig-the link betweeni energy liberationl
and its utilizationi as eontractile tension. This
subject has been recelntly reviewed bv Hajdu
and ILeonard.52
Contractile teimsion in turn, onlee produced,
is manifest only as muscle tension and heat,
tio external work being accomuplished. Evell in
expresses it into the arteries. The amount of
this conversioni of tensioni to work depends oni
existing conditions, particularly onl the anoutLt
amid iiature of the load on the heart.8 When
the load is too great; or if other conditions
KATZ, FEINBERG, SHAF.FER
p)revenlt nmusele shortening,
energy utilization
i(, manifest only as mlusele tensionl and heat.
no external work being accomplished. Even in
this (isometric or, more accurately, isovoluinic) type of contraction. however, shortenilig
of the contractile elements of the heart muscle
fiber still takes place, but, since the volumie
of the heart is niot reduced the only result of
this shortening is the rearrangement of the
shape of the venitriele and a stretchinlg of the
elastic elemienits withini the heart wall, which
are ini series with the contractile elements.
Possible Defects in Energy Transformation Which
Lead to Heart Failure
Oni the basis of the foregoing considerations.
heart miusele failure could, at least theoretically, result from (1) partial failure in energy
liberationi, either at the oxidative level or the
cheimical energy transfer level, or both; '2]
inefficienev of energy utilization in the developmlelnt of tenision; or (3) inefficient conversion of contractile tension into external
wvork. In the last 2 eircuimstaniees, an iniordinate expeimditure of energy would be necessarv in order to maintaini the niornmal capacity
to do " external work.
Impairment of Oxygen Use as a Cause of Heart
Failure
Studies of oxygen usage, and of m-ost of the
comimmoln arbohydrate, lipid and amlino acid
substrates have beeni miade in the normal and
failing heart.54 For the nmost part, these
studies relied on coronary arteriovenous differen-ices aiid simultaneous determiniations of
coronarv flow correlated with parameters of
eardiac effort. Silnce the substrates studied
miiay be transmnuted, stored, or oxidized auid
since their comiplete oxidation may require
anmounts of oxygen differenlt from that consummied in terms of actual measurement,55 sueh
data would not appear to give a true picture
of the rate of substrate utilization within the
heart musele. Oxygen usage, oni the other
hanid, serves as a unceh better index of the
over-all. rate of oxidative netabolism. Since
oxvgen canniiot be stored in sign ifieamit aionrts,
,in the heart muscle, its disappearance rate
Circulation, Volume XXI, Januuary 1960
SYMPOSIUM ON CONGESTIVE HEART FAILURE
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would seem a reliable index of its utilization..
Because anaerobic energy-yielding reactions
are relatively less important in comparison
with the high yield of cardiac aerobic reactions, it is generally held that cardiac oxygen
usage is a good index of the total amount of
eniergy furnished for contraction arid maintenanlce. This is borne out by the good correlation between indices relating cardiac effort
to oxygen usage.
Comparison of the normal alnd failinig heart
reveals little differenlce in the rate of cardiac
oxygen usage.54 Thus, one is tempted to conelude that energy liberation, ineluding transfer of oxidative energy in a fornm useful to
the contraction process, is niormal in heart
failure. This appears to be substantiated by
the lack of differenee in the levels of the various high-energy phosphorus compounds or
energy-sto-age subLitanees betweeni the niormalanid failing heart.56
Attenmpts to gain inisight inlto the mnechanisnm of ceheniical-iechaanical coupling hav-e
beeni beset by mnajor difficulties. Chief among
these is the disparity between the finidings in
nLusele models and in intact muscle.57 Studies
of muscle maodels have showni a utilizationi of
adenosinetriphosphate during contraction and
revealed the relationship of uyosin as anl
adenosinetriphosphatase. Intact muscle, oni
the other hand, shows no discernible decrease
in adenosi.tietriphosphate in a single twitch58' 59
anid there is no apparent differenee in turnover rate of adenosinetriphosphate between.
contraeting and resting muscle. Also, wide
divergencies can be demonstrated when the
rate of hydrolysis of adenosinetriphosphate is
r elated to coontraction in muscle preparations.60 Therefore, it is hazardous in our preSeut state of knowledge to speculate concernling
the role of chenmical-nmechanical coupling in
hleart failure. However, emerging considerations regarding these mechanisms provide
attractive pathways for future exploration of
cause and effect relatiolnships in cardiac fail-
nire.
Apart fromn the possibility of a defect in
energy liberation, the integrity of the conlCirculation, Volume XXI, January 1960
101
tractile protein (actinomyosin) conies into
question in failure of the heart muscle. It is
conceivable that acute or chronic failure
might alter the character of such proteins and
affect muscle response even in the presence of
an adequate energy supply and its utilizationup to this point. Indeed, two lines of investigation suggest that this is inore thani a possibility. Olson and Piatniek61 found molecular
weight changes in cardiac mnyosin after experimenitally induced failure, and Benson et
al.62 noted a decrease in the tension response
of glycerol-extracted myocardial fibers froni
failing hearts. However, the possibility that
changes in elasticity coould explain these results was not excluded in Benson 's experiments.
While evidenee to the contrary seems virtually complete, the possibility still exists that
heart failure, at least under some eircunmstancies, may be caused primarily by a defect
in energy liberation that is not revealed by
neasurements of oxygen coonsumption anid
concentration of high-energy compounds.* ft
myocardial infaretion, in which viable niusele
is destroyed, there canl be no doubt that heart
musele failure is due to loss of liberated energy, and a similar state may be more subtly
in-duced in other disease states of the musele
(as in group 3 above). In cases sueh as these,
the evideniee of a deficit in energy liberationi
will be mirrored in a diminiished cardiac effort. As recovery oceurs, or c oinpensatory
*Onie other concept should be menitionied iii this connection. The heart in situ, as distiniet from the isolated heart or that of the heart-lunig preparationi,
may take up substrate from the blood as ani eniergy
source and pass incompletely degraded products back
into the blood for oxidationi in other organis. While
this process of ebb and flow of substrate amid degraded material must be small normally, the possibility exists that it may be significantly augmentedl
in aiyocardial failure, thereby making the oxygen
consumption of the heart a less perfect index of its
energy liberation. For exaaiple, the cycle of blood
glucose going to the heart and myocardial lactic acid
passing back to the blood may be augmented in heart
failure. This is an actioni which spares the heart,
while yielding energy for it. The above must be
considered only as a theoretical possibility.
102
inechanisms, e.g., hypertrophy of surrounidinig
muscle, conie into play, eniergy liberationi, as
well as heart function, will telid to returil to
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normal.
Experimental studies by anid large however.
have led most reviewers to conclude that it
is the process of energy utilization that is
ablnormal in heart failure. Un-itil cleani experimeintal evidencie to the contrary is forthcoimingo we caiiiiot favor impairment of energy
1 iberation as the ordinary mode of heart
muscle failure. This conelusion appears to
t)e supported by the fact that the external
niiechaniical efficienciy of the heart, the ratio
of externial work done to oxyogen used, is decreased in heart failure.54 Furthermore, it has
beeti shown that measures takien to reverse
failure also serve to restore toward nornmal
this index of efficienicy, both in the aninial
and clinicallyv.3 Unfortunately, this argtmnent
based on chaniges in external mechanieal efficienev mnay be spurious, since the reduction
in cardiac output and increase in heart rate
that accompanv heart failure would lead to a
decrease in external nechanical efficienlcy even
ill the nionfailinog heart.4 4- Thus, it mnay turni
out that the reduction of efficiency is a secondary phenomuenoni accomnpanying chamiges ini
eardiae output amld heart rate rather thaii a
primary feature of heart failure. This matter
caiinot be regarded as settled.
Impairment of Chemical Energy Utilization for
External Work as a Cause of Heart Failure
Externial work-used in the calculationi of
extermial niechani-ical efficienie- really does niot
exemplify the conversioni of cheniical to mnechanical energy appearimng as mnuscle temiSion.'53 In our view, the ideal index to my-o(ardial effort w-ould be the accurate deteriiiiimation: of m-uLsele tenisiomi of the ventricles,
actual externial work being incidenital.
Some imnsight iiito the mechaniisni defect iii
heart failure mnay be revealed by a consideration of the developmeint of temisioli ill coitractilig heart mnuscle. The earliest studies of cardiae miuscle were eoncernied with finidinga
analogies betweeni skeletal amid cardiac imusele
activity-. (). Frank constructed i(dealize(l (urves
KATZ, FEINBERG, SHAFFER
based onl pressure-volumie changes in the cardiac cycle and explained them on the basis of
lenogth-tension changes seeni in skeletal muscle.65 Characteristic curves relating pressure
to volunie were coiistructed for the heart in
diastole aad in systole, in both isoinetric and
isotoiiie contractioni. The aetual pressure-volunie changes occurrilng during a cardiac cycle
were theii superimposed upon this, to represenit the actual expeniditure of energy appearimig as heart work. Later, Starling and his
associates elaborated the gene7ral principles
governinfg conitrol of eniergy expenditure using the nianinialian heart-lung preparation.66
They exteiided Fraimk's observations by relating ventricular emid-diastolic volume (i.e., the
lemigth of the niusele fiber) to the energy set
free in the following systole.
In our owIn previous studies, the pressurevolunie relationships that Frank had demonstrated amid Starling had applied to the mamnialian heart were used to define the viscouselastic properties of the fully relaxed and
fully eontraeted heart.67 The curves so de
rived indicate respectivelv the diastolic aiid
systolic tonie of the heart. Diastolic tone can
affect the emid-diastolic volume and systolic
tonie helps to determine the systolic residue of
the heart.
Further studies by Starliiig and others were
based primiiarily omi nieasurable hemodynamic
variables. Exhaustive iimvestigations were
made of the effects of alterimig vascular resistaniee, venious returmi, anld heart rate upomm
enid-diastolic volume, eiid-diastolic pressure,
anld the extenit of contraction.68 69 The preoceupatiomi of these investigations with hemodvynamici studies of this type led to neglect of
the comicept of temisioii. On the other hat-d,
Wiggers and Katz, 70 in 1928, analyzed the
iintraveiitricular pressure curve and suggested
that the area benleath the isoiiietric portions of
the curve and that part during ejection above
arterial diastolic pressure should be taken to
rel)resenit the "' static effort, " while that beneath the arter ial diastolic pressure during
the ejection portioni of the curve should be
c(:onsidered as aim inidex of 'dyniamic effort."
Circulation, Volume XXI, January 1960
SYMPOSIUM ON CONGESTIVE HEART FAILURE
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This distiiietion served to emphasize the large
differences in tension expenditure associated
with different aspects of muscle contraction
during the cardiac cycle. These concepts of
the character of the heart's effort were interpreted in terms of time-tension relationships
found in skeletal muscle, in which a correlation between oxygen consumption and the
duration of tension development had been
demoinstrated.71
Understanding of funetional relationships
has been materially advalnced by morphologic
considerations. Anatomic studies reveal that
the majority of the myocardial fibers have
both their origin and insertion on the valve
rings, while a few are attached to the chordae
tendineae or follow a circumferential path
around the ventricles.72 These facts added to
the knownl physical relationships governing
pressure and tension in a hollow viscus led to
the realization that, other things being equal,
a ventriele that is initially filled with a larger
blood volume will require augmented contractile tension in elaborating the pressure necessary to open the semilun-ar valves and to
mnaintain it above the arterial diastolic level.
The extent of shortening thereafter and the
relation of ejected volume to end-diastolic
volume will determine the direction and rate
of tension change assoeiated with ejection.
Burch et al.,73 in 195)2, presented an extended theoretical anialysis of these factors,
with special reference to the consequence of
cardiac dilatation such as is seen in heart failure. It was shown that contractile tension
usually decreases in the normal heart duringf
ejection because of the rapid deerease in internal surface area as the heart volume declines, and despite the continuing increase in
pressure from the diastolic level to the systolic
peak. However, when the heart is dilated, as
in failure, ejectioin of the usual stroke volume
is associated with relatively little shortening.
Sinee the decrease in internal surface area is
proportionately less, an increase in contractile
tension may be required under these circuinstances in order to raise blood pressure to the
same systolic peak.
Circulation, Volume XXI, January 1960
103
Aiiother aspect of this same question has
come under investigation in our laboratory74
and that of Sarnoff et al.'5 In these studies,
indices of tension were sought in relation to
the oxygen cost in the intact heart. Evaluation
of blood pressure, heart rate, and cardiac output showed that the first 2 were more closely
related to oxygen requirements than the last.
Thus, for any giveni heart size, blood pressure
may be taken as a direct function of contractile tension per beat, and heart rate as a
measure of the number of times tension is
created. Together they serve admirably as an
index to total tensioni developed over any
period of time. The studies demonstrated directly that minute cardiac output, which receives so much attention in the calculation of
external work anid efficiency, is of minor importance as a measure of cardiac effort, whereas heart rate, which is usually ignored in these
(alculations, is of great importance.
Recently, we approached the problem of
tension conversion to external work and the
energy cost of tension development directly
by measuring the oxygen cost of left ventricular tension in the absenee of external work.76
A fluid-filled balloon placed in the otherwise
empty ventricle permitted the calculation of
tension per beat exerted oni the balloon along
with the concomitant oxvgen cost. The results
in-dicated that oxygen cost is directly related
to energy expenditure as tension per beat. The
further conversion of the developed tension as
external work is a secondary, far less significant factor that is related to the mechanical
advantages or disadvantages dictated by the
range of size and shape of the heart durino
its cycle.
It would seem logical to conelude from the
above consideratioiis that heart failure does
not appear to be related to defects in energy
utilization for tension developmient. Rather, it
would seem that muscle tension in heart failure is not as productive of external work as
in the normal heart. This relative ineffectiveness of muscle tensioni appears to depend on
changes in heart size and shape with heart
failure. Rushmer77 in his elegant studies of
104
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size changes in the intact unanlesthetized animal has emphasized the range of dimensional
changes in various diameters of the nonfailing
heart. Further studies are needed along these
lines, in which attention should be paid to the
role of dilatation in the failing heart, and to
its detrimental effect on the utilization of tension as external work. Perhaps it will turn
out that this relationship fixes the liniit of
dilatation as a compensatory mechaniism.
While it appears that the dilated failinig
heart requires considerablv miore contractile
tension to meet the needs of a given load, no
inidication has been given as to how this dilatation comes about. It was evidenit in the
"Iheart-lung period" that important differenees could be discerned in the response to
load between a fresh and a "tired" heartlung preparation, as well as before and after
treatment with insulin and glucose.78 Primarily, these differences consisted in alterations in respoiisiveness of the heart-a greater
output or aii inereased pressure being noted
iii the fresh heart or the one treated with insulini and glucose independent of an-y conisisteiit increase in end-diastolic volume. These
facts indicate that other mechanisms of cardiac control exist even in the heart-lunig
preparation in which the natural neural and
humoral influences on the heart imusele are
absent. On the other hand, as depletion gradually progresses, the heart in the heart-lung
preparation still responded with augmented
effort to an increase in load, this adjustmeint
now being dependent primarily on the increase in end-diastolic volume. This last mechanism can therefore be considered to be the
basic primitive adjustment upon which other
mechanisms of finer adjustmenit are superimposed.
The failing heart during this early period
of investigation was considered as merely an
enlarged version of the normal heart. Enlargeiment in turn was considered as due in part to
anl increased filling pressure gradient and ini
part to a decrease in diastolic tone. The ability of such a heart to meet the demands for
flow in the body was viewed as depending on
KATZ, FEINBERG, SHAFFER
whether or not it had reached the maximum
size beyond(i whieh output would deeline.
Newer informnationi, based oni a more intact
nondeteriorating preparation subject to the
usual lneural and humuoral stimuli, makes possible a better comnparisoln between normual and
failing hearts in terms of their responsiveniess
to various hemnodynamuic situationis.
The distinctive characteristics of sueh a
preparation mrnay be briefly sunLmarized:
1. The normal heart does niot usually enmpty
with each stroke, in fact as much as 50 peri
cent of the eind-diastolie volumereremains as
end-systolic residue.79
2. The normal heart, at rest, has a characteristic size in relatioim to body size aiid weight
for each species.80
3. The normal heart gemierally has a greater
volume in the supine than in the erect position,64 and has a characteristic relationl of
unuber of beats per minute to stroke volume
(such that the rate is greater for smaller outputs) 81
4. In the face of a growing load, the normnal
heart may first decrease in size-imeeting the
inereased output demands with greater stroke
volume through mobilization of end-systolie
iresidue. Further load may then lead to an
increase in heart rate. Only- when the load is
increased still further does the heart inicrease
in size and briiig end-diastolic volume in-ito
plav.
5. Wild animals of a given species have
larger hearts in relation to their body size anid
weight thani tame omies. This relation has also
been found in trainied athletes as contrasted
with umitraimned individuals.5':' In athletes, there
appear to be a greater end-systolic residue and
a characteristically slower heart rate inl relation to a given work-load. Further, in athletes, ani increase in load tends to cause a
greater stroke volume with miininual iniereases
in heart rate as coimtrasted with the umitraiined
personi in whom heart rate aeceleration is
marked and early.
The failimig heart appears to resenmble the
traiiied heart in the seinse that both are
Circulation, Volume XXI, January 1960
SYMPOSIUM ON CONGESTIVE HEART FAILURE
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elnlarged and both appear to have augmented
end-systolic residues. Superficially the failing
heart would seem to have the same potential
advantages as does the trained heart, i.e., a
lower heart rate for a given output and a
greater reserve of mobilization. However, the
epitome of heart failure seems to be the loss
of these 2 advantages. Systolic residue does
not appear to be available for the augmentation of stroke volume in meeting the challenge
of anl inereased work load. Nor does enddiastolic volume appear to be so effective. Instead, tachyeardia is the mechanism by which
an attempt is made to inerease minute-output.
Because these advantages are lacking, the failing heart has been likened to the heart in the
deteriorated heart-lunog preparatioll, which
also lacks these capacities.82' 83 Like the latter,
the failing heart nleeds a greater eld-diastolie
volunme in order to ilnerease output and overcome augmiented systolic loads, rather than
being able to draw upon end-systolic residue
in the first instance and to react independently of eud-diastolic volume in the second
instance. Apparently this dependence of myocardial effort on end-diastolic volume represents a primitive regulation, or the last resort
of a failing heart.
Contractility and Distensibility of the Heart in
Failure
The capacity to mobilize elnd-systolic volunme amid in general to react independently of
emid-diastolic volume is attributed to that
characteristic of muscle known as contractility. Contractility has so far laeked a sufficienitly precise definition. In the cardiovascular
literature oiie finds it referred to several
phenomelna relating to the responsiveness of
the entire heart or heart muscle strips. A positive inotropic response usually indicates augmnemited force of conitraction after drug or hormonal exhibitioii or nieural stimulation.
Treppe (the staircase effect) 84 encounpasses
augmented contractioni followinig (1) a period
of rest, (2) post-ext rasystolie potentiation,
anid (3) imiereased frequenicy of stinmulation.
Catacholamine exhibition83 and changes in the
Circulation, Volume XXI, January 1960
105
iollic milieu, notably a decrease in potassiuni
ion and an incerease in calcium ion, also augment contractility.86
It appears at present that contractility is, in
its broad sense, a muanifestation of respolnsiveness to many differelnt stimuli, sonie mediated
via the autonomic nlervous system and others
via humoral pathways. Rushmer 's77 efforts to
elucidate this responsiveness in the niormal,
unanesthetized animal must be singled out as
noteworthy and revolutionary.
The mnost important characteristic of con tractility for the purpose of this discussion
appears to be an ability to vary the extent of
shortening for a giveit end-diastolic volume.
More marked shortening in these circumstances has the effect of mobilizing the systolic
residue of the heart. Thus, it would seem that
the failing heart-dependent oni a muinimal
mode of responisiveness-dilated and unable
to mobilize the large systolic residue, lacks
or is relatively deficient in that property of
muscle cojnsidered as conitractility.
Clear experimental evidence relating to differences in contractilitv, or similar properties
(otherwise designated), between the failing
an.d normal heart is not yet available. Perhaps
restating these concepts will stimulate muchneeded research in this direction.
Several recent studies that have provided
further insight into the intrinsic nature of
contractility are reviewed here on the basis
of their potential significance in the understanding of changes in failing cardiac muscle.
Abbott and Mommaerts,87 in a study of the
iiiotropic mechanism of isolated papillary
musele, considered the change in muscle response to be an alteration of the force-velocity
relationship of the colntracting mnechanism.
Hill8s had demonistrated that the velocity of
contractioni is empirically related to the load
that could be defined by a specific characteristic curve. Thus knowing the work-load
and the coniditions of contraction, one can
calculate the velocity. Force-velocity curves
were found not to be superimposable after
inotropic augmentation, implying that the
beat of papillary muscle became both faster
106
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anid stronoyer on stimuiiilationi. Thus, a greater
beat frequelnev shifted the optinmal efficiellcy
of the musele so as to eause a greater veloeitv
of shortening. To quote: "'The heart adjusts
its internal characteristics so that at greater
speeds of action it is optinmallv efficient at
greater speeds of shortening.'87
Alternatively, a change in contractility may
depend oni anl alteration of the "active state."
This alludes to a muscele change that precedes
aind coexists with the aetual contractioni, and
without which a contractile response is imapossible. The "active state" is presuined to be a
state of readiness to conitract that nmust occur after stimiulatiomi atnd before the maniifest
response. The durationi of the active state is
appreciably shorter than the miechaniieal response. It has been showni that an inereased
durationi of the active state leads to a higher
and imore sustained twitch tensioni. Abbott
and Mommnaerts founld that the duration of
the active state was unchaniged or even decreased when the initensitv of contraction was
iniereased.87 Trendelenburg and LUllman89
also failed to find any apparent change in the
duiration of the active state associated with
iniereased stimulation frequenicy or with alteration of the length-tension relationiship.
Niedergerke,j6 however, founLd that a milieu
rich in calcium ioni did increase the duration
of the active state of cardiac muscle.
The special significance of the aetiv-e state
for the intensity of the ensuing contraction
provides an attractive speculation on one possible advantage of cardiac dilatation. Before
stimiulated muscle begins to shorten, the contracting elemenits take up the slack of the
elastic componietits in series with themn. Prior
stretch, which would passively remove this
slack or even stretch the elastic elements,
would perm-it the fuller use of the active state
for the actual act of shorteninog. Thus, there
is an advantage to a certain degree of dilatationi in that the full potential of the active
state for shorteniitng cani be utilized. Tlowever,
such ain advaIntage inay onily be temporary.
Chroniically stretched fibers may lose their
resting tension anid therebv the mechanical
KATZ, FEINBERG, SIIAFFER
advaintage of the stretch, as a result of plastie elongation anld ''creep."" These are essentially hysteresis phenomena and occur after prolonged extension under load, so that
the inlitial length is lnot attained upon release.
Such changes in physical properties may become irreversible in the dilatation of the failinig heart."'9
Contractility is onlly onie inherent property
of the heart. Distensibility is aniother. While
contraetility is associated with the extent, velocity, and force of shortening, distensibility
is associated with the extenit, and rate of
relaxatiov, of a veentriele. The extent of relaxationi has beeni appreciated for some timne
aind labeled as the diastolic tone of the heart.67
The course of relaxation is important in setting the mode of contraction of the heart. The
velocitv anid durationi of relaxation appear
to have special significance in terms of the
rate of fillin-g of the heart when filling tinie is
limiited as in tachyeardia. The phase of active
relaxationi appears to be nmore closely related
to the restitutive chemical processes that are
required for sustained activity. Brewster et
al.,'" have showni that the enzymatic reactions
that oceur durinig relaxation have a large Q,,
and a large eniergy transfer, as would be expected in relationi to chemical-imechanical
coupling. Conitractioni, on the other hanid, is
associated with processes havingc a small Qlo,
usuallv associated with ionic forces and insufficient to account for contraction energy expenditures. Further, it has beeii found that
the metabolic rate in. liastole is related to its
duration.
Hill anid Howarth92 have presented evidenee
that the act of stretching a skeletal muscle
fiber is associated with the addition of energy
to the fiber. Active relaxationi (in terms of
energy exchange) and passive extenision of
the fibers by the inflowing blood thus would
appear to be related. Part of the chemical
energy potemitial imay be lost wheni forees ini
the munsele imesist extemisiomi through ii-complete
relaxationi. Buckley antd her associates93 94
have imiade anl extemisive study of the relaxation process in the mammalian venitriele, parCirculation, Volume XXI, January 1960
107
SYMPOSIUM ON CONGESTIVE HEART FAIILURE
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ticularly with reference to impedalnce anid
compliance during filling. These ternms are
antonyms and relate to the resistance to filling
and the extent to which the ventricle walls
expand upon being filled. The amount of
filling is related not only to the time available
for filling but also to these concurrent changes
in the physical properties of the muscle that
resist or facilitate filling. These impedance
ehanges were related by Buckley et al., to
changes in its viscous-elastic properties-a relationship already noted previously by others
in the consideration of the systolic and diastolic tone of the heart. Most recently, Bucklev
et al.94 found that a decrease in compliance
aiid an increase in impedance occur during
acute heart failure in the dog, changes which
were irreversible. This represeiits another dimension in physical properties, similar to
those considered relative to the systolic phase
of the cardiac cycle. They are likewise subject to change and may be involved in the
process leading to or resulting from cardiac
muscle failure in man.
Conclusions
From all of this it would seem that the
phenomena of heart failure reside in the heart
muscle and are involved in its size, shape, and
the physical properties during relaxation and
contraction that determine its distensibility
and contractility. These last are set by the
metabolism and chemical milieu of the cardiac
muscle, and are primarily physical, chemical,
and biophysical in character. They may be
determined by anatonmie and geometric alterations as well. At present, it would seem that
the energetics of the heart in terms of energy
release and of utilization of chemical energy
for the development of muscle tension are less
often involved in heart muscle failure, than
is the coniversion of tension to external work.
This background has made the development of
heart muscle failure easier to understand. It
would be hazardous to say that the subject
is settled, but it is safe to assume that the directions for further study have been established.
Our purpose has been to review the subject
Circutlation, Volume
XXI, January 1960
of hemnodynamies in coongestive heart failure
as it stands today. The picture of course is
still crude, but the outlines depicting the true
nature of congestive heart failure are dimly
discernible. Future work will doubtlessly
bring it into sharper focus.
Conclusions in Interlingua
Le objectivo del presenite articulo es revistar le
hemiiodynaniica de congestive disfallimiiento cardiac
secundo le stato currente del recerea. Le autores insiste que le ver natura de congestive disfallimeinto
cardiac ben que illo es certo nioni ancora clar, conmencia
al minus devenir recognoscibile in su contornos genieral. Investigationes futur va siil dubita succeder a
focalisar lo plus nettemente.
Super le base del datos jam establite il pare que
le phenomenos de disfallimento cardiac ha lor sito in
le myocardio e es interessate in le dimensiones e le
conformation de illo si ben que comiio in su proprietates physic de relaxation e de cointraction le quales
determina su distensibilitate e su coiatractilitate. Iste
ultimes depende del metabolismo e del chiimismo del
myocardio e es primarimente de character physic,
chimic, e biophysic. Illos etiam pote esser determiniate
per alterations anatomic e geomnetric. Al tempore presente il pare que le energetica del corde i.e. le provision de energia e le utilisationi de eniergia chimiiie in
le disveloppamento de tension niuscular es interessate minus frequentemiiente in disfalliiiento niyocardial que le conversioni de tension in labor externe.
Iste constatationes forni un plus firme base pro le
comprension del disveloppameiato de disfallimento
myocardial. Le autores assere que il esserea riscose
inantener que le question es resolvite sed que il es
permissibile insister que al minus le direction in que
investigationes futur debe avantiar es clarmente establite.
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Circulation. 1960;21:95-111
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