JhCC Vol. 22.No.
1
318
DIRK L. BRUTSAERT, MD, PHD, FACC, STANISLAS
Antwerp. Belgium
Primarydiastolicdysfunctionor failureis a distinctpathophys-
iologicentity. It resultsfrom increasedresistanceto ventricular
tilling, which leads to an inappropriateupward shift of the
diastolic pressure-volume relation, particularly during exercise
(exercise intolerance), The cawes of diastolic failure are inappro-
priate tachycsrdia, decreased diastolic compliance and impaired
systolic relaxation. Impaired (incomplete or slowed) systolic re-
laxation must be conceptually distimgu~he~ from com~asatory
Diastolic failure of the heart is a widely recognized clinical
entity. Whereasmost cases of diastolicfailureare secondary
to systolic failure and are part of the terminal picture of
congestive heart failure, there also exists a primary form of
diastolic failure commonly defined as “a condition with
classic findingsof congestive failure with abnormal diastolic
but normal systolic function at rest” (l-9). Because the first
symptoms of congestive diastolic failirreoft*:noccur during
exercise, exercise intolerance is considered as an early sign
of diastolic failure (10). It is observed as an early event in
many clinicalconditions, such as hypertrophic cardiomyop-
athy (including aortic stenosis and hypertensiilz heart dis-
ease) and ischemic cardiomyopathy. In this sense, diastolic
dysfunction with manifest diastolic failure during exercise
is more common than originally thought (that is, approxi-
mately 40% of all conditions of congestive heart failure
seem to evolve from diastolicfailure). Nevertheless, isolated
left ventricular diastolic failure or dysfunction has been
shown to be associated with a low cardiac mortality rate; at
the same time, it is associated with substantial morbidity
(11).
Because there is often confusion about the use of the
terms dimtole and diastolic firnction or dysfunction, one
should first make clear what component or phase of the
cardiac cycle is under consideration. We therefore first
consider the term dhtole and reexamine the definition of
diastolic failure. We then review some of the known causes
and discuss some therapeutic implications.
Fromthe Departmentof Physiologyand Medicineand Universityliospi-
tal. AntwcrpUniversity,Antwerp, Belgium.
ManuscriptreceivedJuly 22, 1992;revisedmanuscriptreceivedNovem-
ber 2.5.1992,acceptedDecemberI, 1992.
Address: Dirk L. Brutsaert,MD, PhD, Universityof
AntWerp,Groenenborgerlaan171,2020Antwerp,Ee!gium.
CI1993by the AmericanCallege of Cdiology
July1993:318-325
U. SYS,
prolongedsystolic c~~tra~t~~~i&z1
Optimaltherapy will d
drugs.
The heart is a muscular pump. In the same way as in
isolated cardiac muscle, a decrease irhforce and relengthen-
ing during relaxationof an afterloaded twitch are parts of one
activity transient (that is, part of one contraction-~e~axat~o~
cycle [or “systole”]), a decrease in ventricular pressure and
an increase in ventricular volume during early rapid filling
are closely related to this activity transient and should
therefore be considered as part of sirstole (12). On these
conceptual grounds, the term dinstole should be restricted to
the phase during the cardiac cycle that separates two such
consecutive contraction-relaxationtransients, that is, to the
diastasis and the atria1contraction phase, or approximately
the last 5% to 15%of volume change during cardiac fillingon
a pressure-volume diagram (Fig. I, points 3 to 4).
The previous definition of diastolic failure should there-
fore be restated as follows: “a condition resulting from an
increased resistance to filling of one or both ventricles,
leading to symptoms of congestion due to an inappropriate
upward shift of the diastolic pressure-volume relation (that
is, during the terminal phase of the cardiac cycle). Whether
this upward shift of the diastolic pressure-volume relation is
caused by increased pressure for a given vcalumeor by
increased pressure inappropriate or disproportionate to the
increase in volume or whether the shift is symmetric or
asymmetric will not affect the henaodynamicconsequences:
pulmonary wedge pressure will increase (10). Accordingly,
the upward shift of the diastolic pnss:u-e-volume relation
may lead to symptoms of congestion, often at rest but
particularly during exercise, manifesting as exercise intoler-
ance. This shift may ajso lead to subendocardial ischemia
and, if chronic, to remodeling and hypertrophy of the
ventricle.
A common problem in science is the difficula~~ in formu-
lating the appropriate questions. In the publisher;reports on
 A

DECREASEO IMAPPROPRlAW
qlASlOLlC TACHVCARDIA
‘COMPLIANCE

e causes are
d_xlivision of the cardiac cycle into systole IS)
illustrating the causes of diastolic faib-e: CONT
, IC .- iso~oiiimerric coaPracPion:IR =
isovolumetricrelaxation; = pressure; = rapid fillingphase;
V = volume. 1 = aortic valve closure; 2 = mitml vdvk opening; 3 =
end of early rapid filling; 4 = e~d-d~ast~~~. Modified from Brutsaert
and Sys (12).

ary diastolic failure, two basic questions have been

ab~~rm2l~ties of t
result in decreased

all three act in concert.

ure, the eliciting patbo-

efore cohltraction I!? many in-

ventricular relaxation, inc

dominantty caused by ab
may be di2gncsed by so-ca late relaxation measure-
ments, such as a prolongation of tau or a decreased rapid
filling rate. If, however, only the ve;-j early time course of
relaxati@cl is impaired (for example, because of impaired ,part from direct compression
contractile pro ~nter2ctio~ and detachment), meas
ments that into ate this early phase of relaxation, sue
stroke aork, ejection fr2ction, end-systolic pressure-volglme
relation. ;eak neg2Gve first derivative of Ieft rc I# alar
pressure (dP/dt) may be abnormai even in the presence of
norm21 Bate rei2xtitios indexes. In most clinical conditions, ~e~cardia~ pressure, which will be transmitted to the left
however, contraction 2nd relaxation abnorm2!ities are ventricle, wherf. it will ftirther increase the diastolic
 BRUTSAERT ET AL.
320
DIASTOLIC FAILURE
Table1. Various Conditionsof DecreasedDiastolicCompliance
as Causesof DiastolicFailure
Structural and geometric changes of the ventricular wall
Restrictive csrdiomyopathg (interstitial fibrosis. edematous infiltration,
collagen remodeling, amylddosis, hemosiderosis)
Primary and secondary hypertrophic cardio~lyopathy, asymmetric
hypertrophy
Postmyocardial infarction scarring, aneurysm
Endo~%yGZXdia! Co&, i%ii&iSi~SiS
Ischemia (rigor bridges?)
Extraventdcular causes
____;_:_;
_I
@WiCalliiai eu”usion, constriction, venrricuiar
Rikiiiizii ~.VIIJLLOIIII
enlargement)
Right-left ventricular cross-talk
Pulmonarydiseases
pressure-volume relation, with no direct repercussion on
systolic function (17).Equally important and often related to
conditions of pericardialconstraint is the potential functional
importance of right-!eftventricak interdependence in tori-
ditions of acute unilateral right ventricular overload. The
resultlag “cross-talk” may have implicationswith respect to
some more specific clinical conditions or to some forms of
treatment; for example, pulmonary embolismor drug inter-
ventions that act on r.he loading conditions of the right
ventricle may indirectI,*also affect measured left ventricular
compliance during diaztole.
A common cause of diastolic failure is impaired (or
slowed or incomplete) systolic relaxation of the left ventri-
cle. Impaired nlaxation must be distinguishedfrom delayed
or retarded relaxation.the latter condition should preferably
be called prolonged contraction (Fig. 2). Although both
conditions are often barely distinguishable in clinical cardi-
ology, it is important to make the distinction on conceptual
Figure 2. Impaired sysMic relaxation (right)cos.ipared with condi-
tions of prolonged systolic contraction Oefi). Impaired systolic
relaxation, but not prolonged contraction, can be a cause of diastolic
failure. a, b, c = without (a) or with (b, c) physiologic changes in rate
of relaxation; -dP/dt = peak negative first derivative of left ven-
tricular pressure; 7 = time constant of isovolumetric relaxation:
other abbreviations as in Figure I.
‘etayed 1 relaxation slowed
retarded _I relaxalion
incomplete
JACCC Vol. 22, No. :
July 1993:.318-325
grounds and for practical diEgnosticand therap
erations. Whereas impaired systolic relaxatio
pathophysiologic process that is always delete
long run, prolonged contraction is ~~ysi~~~gi
in itself deleterious.
septal The primary event
systok
y prolong ion is a delayed onset
relaxalisii, regardless of MWMIei ir iS accompaiiiedbji pii_
iologicchanges ia the rate of relaxation. An upward shift of
the pressure-v~~~rne~elatiQ~during true diastole is not
observed in cQnditio~sof co
tion; an exception to tkis rule e seen at i~approp~iate~
high heart rates. The caus
k frogs and k&r by Sta
rtrophy, at least d~r~~~t
nary vascular (20-22) and e~docardial (22-27)
(Fig. 3. right) induce similar changes in the
systole. Substances such as angi~te~si~II, ca
(alpha,-agonist activity) a vasopressin, whose
levels may all be increased
tions of heart failure, elicit a similar response in systolic
duration (25). As stated before, the mere prol~~gat~Q~ sf
can be accompanied by moderate (that is, phys-
nges in the rate of co traction or relaxation.
Physiologic modulation in the rate of contraction or relax-
ation will depend on sympathetic drive (28), plasma cate-
cholamines (beta-adrenergicagonist activity) (29), instanta-
neous changes in load during the cardiac cycle (30) and
frequency potentiation induced by changes in heart rate (29),
relaxation. By contrast, the primary
event in impaired systolic relaxation is an inappropriately
decreased rate or decreased extent of relaxation. As a
consequence, relaxation extends into true diastole, with an
upward shift of the pressure-volume relation. Ischemia and
hypertrophy (at least iinthe advanced phase of hypertrophy),
as in aortic stenosis or hypertensive heart disease, are
common causes of impaired relaxation. Nonuniformity of
ventricular performance, which often accompanies these
two clinical conditions, may also constitute a cause of
e impaired reiaxation regardless of the degree and extent of
underlying ischemia or hypertrophy (31). In all of these
clinical conditions, an inappropriately decreased rate or
exient of relaxation may indeed result from disturbances in
the so-called triple control of relaxation; that is, 1) from
impaired activation-inactivation(calcium homeostasis, sar-
coplasmic reticulum pump, contractile proteins); 2) from
excessive changes in load; or 3) from inappropriate nonuni-
formities of load and activation-inaciiva,tionin time and
 ctsofthe three maj~ ulators of cardiac perfor- duiatk of cardiac pa-for
mance on systolic duration of press ime curves of canine left
ventricle (22). For comparable changes in timing of relaxation, the
rate-and pattern of relaxation were influenced d~ffe~e~t~y by the calcium chloride (0.05 mgkg body weight;
three types of modulation. Left ventricular presjurc (LVP) (top), of rise of pressure; left ventricular pressure
first derivative of left ventricula PIdt ;‘?I. ;ine, nid91:)
and phase-plane (d&‘/d? vs. LVP, *ings are displayed. Ir
after
dula- h pm4s, ~odu~a~i~~ of cardiac perfmnance by e
lume helium (eadotheli~m-mediated autoreg~lati0n) (20
(heterometric autoregnlation or Frank Starling mechanism). Com- The endocardial endothelium was functionally inactivated by higd
pared with baseline (big B, loweringleft ventricular volume and power. high frequency intracavitary ultrasound E- ). Compared
pressure (k10w)indwced slightly lower rate bf pressure increase and baseline (+); peak ?eff ventricular pressure and peak positive
early onset of decreaw in left v ricular pressure. As evident from remained unaltered. The decrease in left ventricular pressure was
the phase-plane tracing (hot panel), initial decrease in left induced prematurely and revealed a slightly accelerated cciurse,
ventricular pressure and peak negative dP/dt were slower at the evidenced by a slight increase in peak negative dP/
lower end-diastolic volume, in contrast to the late decrease in left c in left ve~t~co~ar pressureon
ventricular pressure, which was faster (i.e., projected below control wel)slightlybelo;wthe baseline

space. An extensive discussion of the triple control of ; this may result fro
tarling mecha~ism~, myocaudral h
plasma levels of various component
sin), among other factor5. In the
inappropriately decreased rates of relaxation
impairment of relaxation may disturb the clinical picture.
ing on a given disease and on the instant during the devel- Along with decreased compliance and increased rt rate,
opment cf tha: disease, these two features can be present impaired relaxation may result in an upward s of the
separately or in combination. This can be best illustrated by ress~re-volume relation g diastole (Fig. 2, rig
examining the ~atho~hysio~ogicevolution of pressure or resulting in exercise lntoler Hn the third phase of Figure
volume overloading, or both, of the left ventricle (as in Fig. 4, conco~~ita~tsystoolicfailure develo s. Systolic failure
4). Of importance is the general pattern trf the pathophysio- results in ioss of systolic com~e~sat~o~(that is, in decreased
logic evolution with time and the pattern of the ~~divid~l co~tract~~~ty during contraction and early
pressure e~rves in each cardiac cycle. Znthe evolution of e capacity to piOlOnU& systole; inst
pressure and volume overloading with time, several phases 4, the onset of relaxation is often induced ~rerna~~r~~y
can be distinguished. 7%: initial phase is compensatory, with further complicates the already existing clinical picture of
typical prolonged corztraction and, hence, delayed or re- diastolic failure.
 BRUTSAERT ET AL.
322
!%4STC!L!C FAILURE
systolic compensation
with diastolic failure
compensalory,prolonged contraction compensatory
(delayedlrelarded relaxation) and
impaired decreased
relaxation 6ompliance
. ACE.lnhlbllw~
. dlwotko: load 1
Figure 4. Successivephases during the pathophysiologicevolution
of pressureor volume overloading, or both, of the left ventricle.
Only pressure (P) vs. time curves are shown.The P curve in full is
the baseline P curve before overloading. ACE = angiotensin-
converting enzyme;ANF = atria1natriureticfactor; CAMP= cyclic
adenosine 5’-monophosphate; cGMP = cyclic guanosine S-
monophosphate;NEP = neutral endopeptidase;PDE = phospho-
diesterase;TnC = troponin C. In the data at bottom, 2 = increase
and I = decrease.
In patients with ischemic cardiomyopathy, these three
phases may, at a myocardial level and at any given time
during the pathogenesis, develop simultaneously and inter-
act with one another at the ventricular level. This may
explain, at least in part, why diastolic dysfunction in differ-
ent types of experimental and clinical myocardial ischemia,
such as coronary occlusion, rapid pacing in the presence ol”
coronary stenosis, multivessel coronary heart disease,
reperfusion and stunning, may be rather complex and not
easily predictable.
Accordingly, a!though it is clear from the latter two
examplesof hypertrophic and ischemiccardiomyopathythat
the causes of diastolic dysfunction and failure are multifac-
torial in most cardiac diseases (that is, based on a combina-
tion of the three major causes described [Fig. I]), these
pathophysiologic concepts should be kept in mind when
developing a diagnostic and therapeutic strategy.
Implicatioas for the evaluationof relaxation. Figures 3
and 4 illustrate that a full evaluation of systolic relaxation
(that is, of isovolumetric pressure decline and early rapid
filling), should encompass 1) measurements or indexes of
i de of pressure decline and early rapid filling(peak negative
JAW Vol. 22, No. I
July 1993:318-32.5
prolonged
I
I
urnetric relaxation t
rate); 2) measurements of th
rate) of the latter rate indexe
patterns, including early,
ltaneous measurem
longed contraction and of impaired relaxation. The need to
examine rate patterns during the entire course of relaxation
has been emphasized by us before (12). This point is also
obvious from phase-plane dP/dt versus pressure analysis
(Fig. 3). where the rate of early pressure decrease, peak
negative dP/dt and rate of late pressure decrease are re-
vealed as three distinct aspects of relaxation. In most cases,
peak negative dP/dt results from the transition from early to
late rate of relaxation and may therefore not be representa-
tive for the entire process of relaxation. Moreover, early and
late relaxation rates may be affected differently and may
oiren change in opposite directions (30).
By extension, these measurements of systolic perfor-
mance during relaxation should, in many clinical conditions
or after various pharmacologic interventions (32), not nec-
essarily be expected to correlate with measurements of
diastolic function, such as diastolic pressure-volume rela-
tions.
r treating patients w
to improve exercise tolerance by dimin
upward shifts in the diastolic pressure-volume relation
(Fig. 5). Although various drug regimens have been tested,
JACC Vol. 22, MO. I
July 1993:318-325

Treatment with bib-0

ina ropriate
ate a relation to reiaxairvn a
Pachycardia

dependsupon
ing in three successive
/\
type phase
of during
cardiac diastolic
disease failure
ng on the relative contribu-
:atl ion of drug therapy for the treatment of diastolic tion of each one bases on ve~tr~c~~a~perfor-
failure. Abbreviations as in Figures I and 4. mance at any given mo

no specific therapy is available.

on the basis of the preceding classification of three cause5.
ould similarly conceive three classes ofpotential drugs.
hen inappropriate heart rate is the
rugs are the treatment of
g agents, calcium channel
conditions (such as atriai
a\‘p 311
fi.br:!!ation). digitalis IL.. _ .._ beer! sncressfti? in imprr?ving
exercise tolerance due to primary diastolic failure. There
have been several recent developments in such drugs. Some
new molecules are potentially interesting with specific
bradycarlic properties but, unlike the other drugs of this
type, are devoid of direct inotropic actions on timem;‘ocar-
dium (33). Ideally, these drugs should preferentially sup-
press inappropriate increases in heart rate during exercise,
with little or no effect on heart rate at rest.
Little attention has been directed tow ’ the treatment of
fundamental changes in myocardiai co
the recent introduction of the concept 0
action on
drugs. Diuretic drugs consistently improve exercise toier-
ante with little change in systolic ~e~orma~ce~ probably
directly through their effects on both right and left ventric-
iastolic loading conditions as ;Nell as indirectly by
reducing pericardial constraint on the left ventricle and on
ventricular cross-talk (10,38). Calcium channel blockers
‘hitropic is derived From the Greek words AM&i, meaning lOOSk
releasing. ransoming, means of letting. deliverance from guilt. redemption of
mortgage or pledge, emptying. evacuation, emission of semen. unraveling,
softeningor divorce, and ~pono(,ir. meaning turn, direction. way. manner or
fashion. The tetm hitropic was coined by Phyllis B. Katz to mean predom-
inantly acting (positively or negatively) on the relaxation of the keart both as
muscle and as pump. The major advantage of the term /~siii’nPif. (that is. its
potential usefulness as a general term to describe interventions that preferen-
tially act on relaxation) unfortunately has the same limitations as the term
hotropic for thecontraction phase. In particular. it lacks SUffiCient SPeCifiCitY

particular in the prevention 3f cardi brosis and regression for the different phases to which the term is meant to relate during relaxation.
Moreover. does it refer to changes in onset. in speed. in extent. or to changes
of hypertrophy, has emphasized potential use of so- jn the time pattern ofrelaxation with little changes in onset. in peak speed or
called remodeling drugs (35,361. For example. various extent. or a:\ ofthese? Does it refer tc kactivation. or does it also incotpot3te
angiotensin-converting enzyme inhibitors and, more re- effects medi,,,ted through changes in loading? (11).

324 BRUTSAERT ET AL.
DlASTOLIC FAILURE
have been shown to improve exercise intolerance in phase?
I and II shown in Figure 4 for still largely unknown reasons
(including relief of ischemia, decrease in intracelhdar Cd-
cium ioR overload and improvement of inappropriate non-
uniformities [39-421)but are in our opinion expected to be
deleterious in phase III. Nitrates, nitroprusside and related
molecules have been shown to consistentiy decrease the
diastolic pressure-volume relation (43,44)and therefore to
improve exercise tolerance (10).A diminisheddiastolic load
of both the ieft and the righ; ventricle and decreased peri-
cardial constraint have been invoked to explain this benefi-
cial effect. Equally important but largely overlooked in all
previous studies, however, is the direct Sect cf nitrates+
nitroprusside and related molecules in abbreviating systolic
duration, with no effect on contraction dynamics, by increas-
ing myocardial intracellular cyclic guanosine Y-monophos-
phate level (45).Such an effect could be particularly benefi-
cial during phase II of the example shown in Figure 4.
Similar to nitrates and nitroprusside. atrial natriuretic factor
(45,46)and neutral endopeptidase inhibitors, which inhibit
the breakdown of atria1 natriuretic factor, would at least
theoretically also be expected to be beneficiaiin the treat-
ment of diastolic failure. Partial beta-agonistsmay slightly
shorten the duration of contraction, with little change in
heart rate owing to the concomitant beta-blocking proper-
ties. Such treatment could be advantageous in phase II,
where it would suppress excessive systolic compensatory
prolongation while simultaneously accelerating the rate of
relaxation. The latter drug actions would be deleterious,
however, during monotherapy in the terminal phase of
combined systolic and diasto!ic failure (47). For similar
reasons, as well as for their vasodila,torproperties, phos-
phodiesterase inhibitors may also decrease the diastolic
pressure-volume relations, thus improving exercise toler-
ance in patients with diastolic fnilure ‘duringphase II, but
should be given with caution in phase III.
As explained b&ire, in many diseases (for example,
ischemic cardiomyopathy and, more conclusively, when in
combination with pressure-overload hypertrophy [13]), the
somewhat arbitrary but conceptualiy useful subdivision into
the successive phases shown in Figure 4 is not always easily
appreciated because various segments of the ventricular wall
may undergo successive phases at different moments and at
different speeds. Here, the efficacyof a drug will depend on
the relative contribution of any one of these phases present
in the various segments of the ventricular wall at any
moment during pathogenesis,
Of interest, drugs with a positive or a negative Iusitropic
action in a given clinical setting will, in other conditions, not
necessarily act as positive or negative lusitropic “drugs.”
VENOUS calcium-sensitizingdrugs (48) as well as sodium
channel openers (49), have often, but erroneously, been
referred to as negative lusitropic because of their contrac-
tion-prolongingeffect. These cardiotonic drugs might indeed
be less desirable in phase KIof the example shown in Figure
4. During phase III, however, and in combination with
JACC Vol. 22, No. I
July 1993:318-325
a~giote~si~-convertingenzyme
cium or sodium sensitizationm
and, hence, be positive lusitropic.
agonists and calcium channel blockers might,
stated, be useful in phase HIbut not in phase
words, there is no single standar
treatment of diastolic failure.
compensatory prolonged contraction (delay
relaxation). Treatment of diastolic failure
feasible but necessitates a clear understanding of the etiol-
ogy, pathogenesis and pathophysiology of the ~~deriyi
cardiac disease. Optimal therapy will depend on the type
disease, on the phase during the pathophysiologic evolution
of the disease and on the coexiste ative contribu-
tion of various CQrn~e~sato~y or satory mecha-
nisms. This often requires a comprehensive analysis of
hemodynamics ifor example, with combined, echocardio-
graphic and Doppler studies), completed, whenever neces-
sary, by catheterization, both at rest and during exercise.
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