Journal of Cardiac Failure Vol. 3 No.
3 1997
Review
Diastolic Dysfunction in Heart Failure
DIRK L. BRUTSAERT, MD, PhD, STANISLAS U. SYS, MD, PhD
Antwerp, Belgium
Diastolic dysfunction and diastolic failure of the heart
have become widely recognized clinical entities. Where-
as most conditions related to diastolic dysfunction and
failure are the mere consequence of systolic cardiac fail-
ure, there also exists a distinct primary form of diastolic
failure (1-4). Primary diastolic failure occurs in a large
variety of clinical conditions, for example, coronary
artery disease, systemic hypertension, diabetes mellitus,
aortic stenosis, hypertrophic cardiomyopathy, infiltrative
cardiomyopathies, and endocardial fibroelastosis. The
underlying pathologic processes include myocardial
ischemia, hypertrophy, and fibrosis, all increasing signif-
icantly with age. In clinical cardiology, primary diastolic
failure has been commonly defined as a condition with
classic findings of congestive heart failure with near-nor-
mal rest systolic function but with predominantly dias-
tolic dysfunction (5). Diastolic failure of the left ventri-
cle is an early event that occurs more commonly (30% in
some series)--at least in the elderly population (6,7)--
than previously thought and is often manifest as pul-
monary congestion and dyspnea during exercise, that is,
exercise intolerance (8). With respect to left ventricular
(LV) diastolic cardiac failure, "exercise intolerance"
ought to be interpreted in a strict sense, that is, exercise
dyspnea caused by pulmonary congestion; it does not
incorporate exercise-induced muscular fatigue or physi-
cal exhaustion. The latter symptoms of chronic systolic
cardiac failure have been ascribed to impaired skeletal
muscle metabolism resulting from deconditioning,
cytokine activation, deficient endothelial vasodilator re-
sponse, and loss of anabolic function (9-11).
From the Department of Physiology and Medicine, University of
Antwerp, Antwerp, Belgium.
Reprint requests: Dirk L. Brutsaert, MD, Department of Physiology
and Medicine, University of Antwerp, Groenenborgerlaan 171, 2020
Antwerp, Belgium.
Manuscript received March 12, 1997; revised manuscript received
July 2, 1997; revised manuscript accepted July 3, 1997.
1997 Churchill Livingstone Inc.
225
The criteria that help to identify abnormal LV dias-
tolic function in the presence of normal ventricular sys-
tolic performance are, however, insufficiently clear to
fully comprehend the above clinical definition (7). As a
consequence, the concepts of diastolic dysfunction and
failure with normal ventricular systolic function are still
not well understood by most clinicians, and the diagno-
sis, the presumed clinical prevalence of which varies
widely from 13 to 74% (7,12), as well as the natural his-
tory (13) and prognosis (14), continue to cause major
controversies, the main reason being that many--mainly
clinical--investigators, on either empirical or historical
grounds, persist in using different criteria to define nor-
mal systolic and abnormal diastolic function (15). For
example, the definition of diastole and diastolic failure
differs depending on whether the heart is considered as a
pump rather than as a muscular pump or whether cardiac
hemodynamics are evaluated as a function of time or
as pressure-volume relations. A clear pathophysiologic
definition is mandatory, however, as the management of
patients with primary diastolic dysfunction or failure is
very different from the management of patients with pri-
mary systolic failure (5).
The physiologic concepts on which the subsequent
sections are based have been outlined in detail in an
exhaustive review on the subject (16). For the erudite
clinical and basic scholar, reading of this text is highly
recommended to fully appreciate what follows.
Definition of Diastole: The Heart as a
Muscular Pump
The heart is a combined muscle and pump system. To
evaluate the mechanical performance of this muscular
pump, one should take into account the mechanical prop-
erties of the myocardium as well as those of the system
as a pump. In Figure 1, the force and length traces of an
afterloaded isotonic twitch obtained from isolated cardiac
muscle have been appropriately synchronized on a time
scale with the pressure, volume, and mitral flow curves of
226 Journal of Cardiac Failure Vol. 3 No. 3 September 1997
an ejecting left ventricle. Despite the auxotonic loading
conditions in the ventricle, there is a striking resemblance
of the time patterns between force and pressure traces and
between length and volume traces, the speed of the latter
two events during relaxation exceeding by at least three
to four times the speed during contraction. Importantly,
the decrease in force and relengthening of the muscle
during relaxation are part of a single activity transient,
that is, a single contraction-relaxation cycle or muscular
"systole." To muscle physiologists, the subsequent rest
constitutes muscle "diastole." Similarly, fall in pressure
during isovolumic relaxation and increase in volume dur-
ing early rapid filling of the ventricle are closely related
to these myocardial events and, hence, to muscle systole.
Diastole then encompasses diastasis and the atrial con-
traction phase. On a time scale, the duration of diastole
depends mainly on heart rate and, to some extent, as we
will see later, on the duration of systole. Together, these
two variables determine the systolic-to-total duration
ratio. At normal rest heart rates, diastolic duration usually
corresponds to approximately 50% of the total duration
of the cardiac cycle. By contrast on a volume scale as in a
pressure-volume diagram, diastole represents only the
last 5-15% of ventricular filling (points 3 to 4 in Fig. 1).
f \
i .j
Fig. 1. Cardiac cycle of the heart
as a muscular pump. Comparison
of muscle (f = force, 1 = length)
and pump (P = pressure, V = vol-
ume, F = mitral flow). The simi-
larity between the corresponding
time (t) traces led to the inclu-
sion of isovolumetric relaxation
(1R) and rapid filling phase
(RFP) into the relaxation part of
systole. As a consequence, dias-
tolic dysfunction or failure can
be defined as an inappropriate
rise in the diastolic pressure-
volume relation during exercise
or at rest, respectively. Possible IC EJECTIONI IR]RFF~
causes of diastolic dysfunction
or failure are impaired (systolic) CONTRACTION i~RELAXATION COMPLIANCE I
relaxation, decreased diastolic
compliance, and inappropriate I s
tachycardia or mismatch of sys-
,l
tolic to total duration.
However logical and important these concepts may be,
many clinical investigators, for historical and empirical
reasons, remain somewhat reluctant to incorporate them
in their routine vocabulary. Although we understa)ld that
nonphysiologists do not wish to take a particular stand on
where exactly systole ends or diastole begins, this unfor-
tunate habit continues to foster controversy about diagno-
sis and therapy of clinical conditions with diastolic
229dysfunction and failure. Regardless of this semantic
discussion the one important feature to remember from
the above considerations is that both pressure fall and
early rapid tilling (ie, about 85% of the volume change on
the pressure-volume diagram) are inherent parts of the
active relaxation process of the muscular pump. Similarly
as for the systolic contraction phase, that is, for pressure
rise and ejection, relaxation of the heart as a muscular
pump is a reflection of the interaction between loading
conditions and myocardial (in)activation processes (con-
tractile proteins and Ca 2+ homeostasis), both modulated
by some degree of nonuniformity in space and time. It
would therefore be helpful if disease processes causing
abnormalities in either pressure fall or early rapid filling
be considered separately as dysfunction or failure of ven-
tricular relaxation. As already stated above, the terms
MUSCLE
P
PUMP
141
2
tt
V
inappropriate rise
ATRIAfi in diastolic P-V
ICONTR
IASTOLiCDYSFUNCTI
D I
1
inappropriate
tachycardia
 Diastolic Dysfunction in Heart Failure
diastolic dysfunction and diastolic failure should be
restricted to diastasis and the atrial contraction, that is,
the very last portion on the pressure-volume diagram
(Fig. 1, points 3 to 4).
Definition of Diastolic Failure
Taking the above conceptual approach, we suggested
that genuine diastole consists of diastasis and atrial con-
traction (ie, the last 5-15% of ventricular filling). Dias-
tolic dysfunction and diastolic failure then refer to
disease processes that shift the end portion of the pres-
sure-volume diagram upward so that LV filling pres-
sures are increased disproportionally to the magnitude of
LV dilation. Accordingly, LV diastolic failure should be
defined as a condition resulting from an increased resis-
tance to LV filling and leading to symptoms of pup
monary congestion caused by an inappropriate upward
shift of the diastolic pressure-volume (or pressure-
dimension) relation first during exercise (diastolic dys-
function) and later at rest (diastolic failure) (Fig. 1, Table
1). This definition embodies both a pathophysiologic
aspect (the inappropriate shift in AP/AV), and a clinical
aspect (that the shift is manifested through symptoms of
pulmonary congestion and exercise-induced dyspnea).
Accordingly, based on the above definition the single
most reliable and most powerful measurement of LV
diastolic dysfunction and diastolic failure is the upward
shift of the diastolic portion (Fig. 1, points 3 to 4) of the
LV pressure-volume or pressure-dimension relation.
This shift may be reflected by an increase in related mea-
surements, for example, pulmonary capillary wedge
pressure (17), transmitral Doppler A-to-E ratio, A wave
on the apexcardiogram.
Causes of Diastolic Failure
Causes of diastolic failure are multiple and can be
subdivided into (1) inappropriate tachycardia resulting in
inappropriate abbreviation of diastolic duration, (2) a
decrease in (passive) myocardial or ventricular diastolic
compliance, and (3) impairment in (active) LV (systolic)
Table 1. Definition of Left Ventricular Diastolic
Dysfunction and Failure
Diastolic dysfunction A condition with increased resistance to
filling of the left ventricle, leading to an
inappropriate rise in the diastolic (ie, end-
portion) pressure-volume relation and
causing symptoms of pulmonary
congestion during exercise.
Diastolic failure A condition with increased resistance to
filling of the left ventricle, leading to an
inappropriate rise in the diastolic (ie, end-
portion) pressure-volume relation and
causing symptoms of pulmonary
congestion at rest.
Brutsaert and Sys 227
relaxation, that is, impaired isovolumic pressure fall or
impaired early rapid filling (2). Importantly, whereas
these latter impairments may lead to the upward shift in
the diastolic portion on the pressure-volume diagram
and, hence, to diastolic dysfunction and failure, impaired
ventricular (systolic) relaxation should in the absence of
such shifts not be called diastolic dysfunction or dias-
tolic failure. Such late systolic abnormalities during
relaxation may well be the early manifestation of immi-
nent systolic dysfunction.
Inappropriately high heart rate as a cause of diastolic
dysfunction and diastolic failure does not merely follow
from the inappropriate abbreviation of diastolic duration
(ie, of diastasis and atrial contraction), but refers in addi-
tion to conditions where prolongation of ventricular sys-
tole becomes critical at a given heart rate, that is, when
there is a mismatch in the systolic-to-total duration as,
for example, at high pressure or volume loads (see
below).
Impaired (Systolic) Relaxation as a
Cause of Diastolic Failure
On conceptual and experimental grounds, ventricular
pressure fall and early rapid filling have been considered
part of the (systolic) relaxation process of the heart as a
muscular pump. Identifying late systolic measurements
or derived indices related to ventricular relaxation with
diastole (18), is, therefore, conceptually incorrect. Only
in specific circumstances may these late systolic events
during ventricular relaxation eventually lead to genuine
diastolic dysfunction and failure as defined above.
For late systolic events during ventricular relaxation to
be identified, however, as abnormal or pathologic, it is
essential that one first differentiates between prolonged
contraction and impaired relaxation (Fig. 2). This dis-
tinction will follow from a close analysis of timing and
rate of relaxation indices.
Prolonged Contraction. Prolonged contraction is due
to a delayed or retarded onset of relaxation. It is the
physiologic, often compensatory, response to pressure
and volume loading of the ventricle (heterometric
autoregulation), to various neurohormones and drugs and
heart rate (homeometric autoregulation), and to cardiac
endothelial activation (endothelial autoregulation) (Fig.
2, left). Although at very high afterloads, close to peak
isovolumetric ventricular pressure, onset of relaxation
may either be unaltered or occur slightly earlier, the
larger remaining part of the relaxation phase remains
shifted in time. Concomitant variations in relaxation rate
(dP/dt-, tan, isovolumic relaxation time, dV/dt, Doppler
E wave, time to peak filling rate, ' etc), if present, should
be viewed as mere epiphenomena and are, in general,
quite unpredictable.
Figure 3 depicts representative examples of the three
types of autoregulation with their effect on systolic dura-
228 Journalof Cardiac FailureVol. 3 No. 3 September 1997

l t -

delayed ? relaxation slowed ? relaxation

retarded incomplete
or or
! PROLONGED CONTRACTION, I i IMPAIRED RELAXATION !
MODULATION OF SYSTOLIC DURATION CAUSES
(= dominant, compensatory, physiological)
* stages 2 and 3 hypertrophy
heterometric autoregulation
* ischemia
- pressure-volume loading (CL vs RL)
. , ,

- stage 1 hypertrophy
~' homeometric autoregulation
- neuro-humoral, drugs
MECHANISMS
* inappropriate loading
angiotensin 11 G Ca +, digitalis
-pressure-volume overloading
alpha-agonists beta-agonists
* inappropriate inactivation
vasopressin
- impaired Ca ++ homeostasis
heart rate
-

(Cat overload, impaired sarcopl, retic.)

* cardiac endothelial autoregulafion
- impaired affinity of contractile proteins
(cytokines, Et, NO, PGI 2 . . . . )
* inappropriate non-uniformity of loading and
MODULATION OF RELAXATION RATE inactivation in space and time
(= epiphenomenon)
"~ secondary to changes in systolic duration
* instantaneous changes in relaxation loadings (P_L)
* neuro-humoral, heart rate
Fig. 2. Prolonged contraction is not impaired relaxation. Prolongedcontraction--or delayed onset of relaxation--causes an increase
in the duration of systole as indicated by the dotted lines in the pressure (P) and volume (V) traces on the left. This compensatory and
physiologic modulation of systolic duration can result from a number of different heterometric, homeometric (O, prolongation; Q
abbreviation), and cardiac endothelial types of autoregulation. These may be accompanied by substantial but often divergent changes
in the relaxation rate (b and c versus a). Impaired relaxation, illustrated by slower (inappropriately decreased rate) and incomplete
(inappropriately decreased extent) relaxation (dotted lines on the right), is pathologic and leads to diastolic dysfunction or failure.
Causes of impaired relaxation can be interpreted in terms an impaired triple control of relaxation (16,19), that is, inappropriateness of
loading, inactivation, or nonuniformity. CL, contraction load; RL, relaxation load.

tion and on relaxation rate, both in isolated cardiac mus-
cle (Fig. 3, top) and in the intact left ventricle (Fig. 3,
bottom). All three types of autoregulation are character-
ized by consistent changes in systolic duration. Less
consistent are the alterations in relaxation rate. For
example, for identical systolic prolongation with
increased loading (Fig. 3, left) and with cardiac endothe-
lial activation (Fig. 3, right) the two changes in peak
relaxation rate are unpredictable and opposite.
These features are illustrated further in Figures 4
(20-23), 5 (23), 6 (24,25), and 7 for changes in early
loading (heterometric autoregulation), that is, in after-
load, preload, and (contraction) load clamp. With all
these load manipulations, systolic duration consistently
 Diastolic Dysfunction in Heart Failure Brutsaertand Sys 229

I
F/dt mN/mm 2,
I MUSCLE!

-500

: O R C E mN/mm

50

ID

. V P mmH! IPUMPI
/ -EE 5"x~ ,

IP/dt mmHgL,

I
Fig. 3. Left ventricular systolic duration and left ventricular relaxation rate: effects of heterometric, homeometric, and cardiac
endothelial autoregulation. Effects of the three major types of autoregulation on the time course of force and left ventricular pressure
(LVP) and time derivatives (dF/dt and dP/dt) during an isometric twitch in isolated cardiac muscle (top) or during systole in in vivo
canine heart (bottom). Note that heterometric autoregulation (left) and endothelium-mediated autoregulation (right) consistently
modulate systolic duration; that is, a higher end-diastolic length (EDL) or volume (EDV) and the presence of an intact endocardial
endothelium (+EE) increase systolic duration. Yet, they do not affect peak relaxation rate in the muscle but induce divergent changes
in peak relaxation rate in the pump, that is, an increase and a decrease, respectively. These changes in peak rates are hardly pre-
dictable and may vary from one animal or from one experiment to the other. By contrast, increased contractility as, for example, by
extracellular calcium (middle, homeometric autoregulation), consistently increases peak relaxation rate, but with relatively minor
effects on systolic duration. Homeometric autoregulation, in general (see also Fig. 2, left), can induce either abbreviation of systolic
duration, or prolongation, or little changes as in the present example.

varies by more than 30% due to shifts in time of the
relaxation phase (Fig. 4). In contrast to the consistent
and reproducible changes in systolic duration, concomi-
tant changes in relaxation rate are in all the above exam-
ples unpredictable, often divergent, and provide, in gen-
eral, little further information. Moreover, during the load
manipulations in Figure 5, systolic duration varied by
more than 30% when early and late aortic occlusions
were compared, but neither dP/dt- nor tau were affected.
The marked prolongation of pressure generation dur-
ing the second half of ejection (24,25) in Figure 6, to far
beyond the timing of the pressure decline as anticipated
from the superimposed isovolumic beat at the smaller
peak systolic volume, is the mere consequence of the
combined effects of (1) maintained myocardial force
generation due to sustained high cooperative activity at a
crossbridge level and (2) the late-ejection reversal of the
pressure gradient caused by the momentum of the blood
column in the outflow tract (26,27). This causes the
(relaxation) loading faced by the ejecting ventricle to
transiently decrease to below the force generated by the
ventricular wall, thereby unloading the ventricle during
late ejection. The ensuing prolongation of systole con-
trasts with the abbreviation of systole when the (relax-
ation) loading was augmented during this late phase of
ejection (Fig. 5, bottom).
230 Journal of Cardiac Failure Vol. 3 No. 3 September 1997

steady-state
test beat -.-}
LVP m m H g

LVP m m H g LVP m m H g
18o
high EDP

~ 120
y
t .:3
0 '

VOLUME ml 6O
TIME ms TIME m s

0.65 TIME m s

IAFTERLOAD] PRELOADl LOADCLAMP1

rabbit dog dog
Fig. 4. Effects of heterometric autoregulation on left ventricular systolic duration and left ventricular relaxation rate. Increases in
loading during the contraction phase, caused either by changing afterload or preload or by a load clamp (by abrupt occlusion of the
ascending aorta), induce compensatory increases in systolic duration. Time courses of left ventricular pressure (LVP) in these physio-
logic conditions consistently show a substantially delayed onset of the relaxation phase, that is, by more than 30% of total systolic
duration. [Afterload from Slinker et al. (20) and preload from Gillebert and Brutsaert (21), with permission. Load clamp modified
from Brutsaert and Sys (23), with permission.]

Figure 7 summarizes changes in systolic duration and
in relaxation rate, as published by various authors over
the past two decades (15,16,20,24,25,28-51), for in-
creases either in contraction loadings (CL), that is, pre-
load or afterload, or in various relaxation loadings (RL).
Depending on the experimental (Fig. 7) or clinical (52)
condition or on the change in systolic duration, either an
increase in relaxation rate or a decrease or no change at
all may be observed. For these reasons, measurements of
relaxation rates are, in general, quite unreliable for eval-
uating late systolic cardiac performance unless normal-
ized for changes in systolic duration. Although such nor-
malized relaxation rates have, in our opinion, as yet not
been published, we anticipate that interpretation of relax-
ation rates will remain difficult as these depend in a very
complex fashion on the interaction of
1. the instantaneous force in the ventricular myo-
cardium and the loading handled by the ventricle;
2. the load distribution and pattern during early and
late ejection, in particular, the relative contribution
of CL versus RL (Figs. 5, 6) (6,32);
3. the substantial shifts in time, as described above
(up to 30% of systolic duration) (Figs. 4-6) of the
instant during systole at which these rates are meas-
ured;
4. the degree of nonuniformity in space and time of
loading and inactivation, being generally more pro-
nounced during ventricular systolic relaxation than
during contraction (16,53--60); and
5. the auxotonic loading conditions during pressure
fall and early rapid filling.
Surprisingly, variations in systolic duration are quite
consistent despite anxotonic loading and despite often
important nonuniformities during ventricular relaxation.
By contrast in these same conditions of auxotonic load-
ing and substantial nonuniformities, relaxation rates can
no longer be interpreted in terms of simple mechanics of
a muscular pump and are, therefore, of doubtful diagnos-
tic value. As most clinicians persist in measuring rates
(dP/dt-, tau, isovolumic relaxation time, dV/dt, Doppler
E wave, time to peak filling rate) to evaluate pressure
decline and early rapid filling during ventricular relax-
ation, the above considerations must be taken into
account as major obstacles in the area.
Within an appropriate range of relaxation rates, pro-
longed contraction normally does not shift diastolic pres-
sure-volume relations upward (Fig. 2, left, inset) and,
therefore, does not normally lead to diastolic cardiac
dysfunction and failure. It may, however, do so at high
heart rates when, despite the heart rate-induced systolic
abbreviation, a compensatory prolonged systole becomes
the limiting factor for filling (mismatch of the systolic-
to-total duration at any given heart rate), even when
no intrinsic relaxation abnormalities are present. Either
 Diastolic Dysfunction in Heart Failure * Brutsaert and Sys 231

,VP mmHc
Fig. 5. Contraction versus relax-
ation load clamps on left ventric-
180
CL
120
ular systolic duration and left
ventricular relaxation rate. Left
5000
m
ventricular pressure (LVP) and 60
dP/dt-versus-time and phase
plane loops of dP/dt versus LVP o
were obtained from in vivo eject- LP/tlt mmHgh
ing dog heart. Control beats 5000
(solid lines) are compared with
ascending aortic occlusion beats
(dotted lines). Despite negligible
effects on relaxation rate (meas-
o ~'"", 200 -5000

ured by dP/dt- or tau) in this

experiment, aortic occlusion
before ejection (CL, contraction -5oo~
load) and during the second half I .VP rnmHt.
of ejection (RL, relaxation load)
markedly affected overall (from
16o
RL
CL to RL) systolic duration by 12o
25 to 30%, by inducing either
delayed (for CL) or premature ]P/d
6000
(for RL) onset of relaxation, oo
respectively. This experiment
also illustrates that evaluation of o
LV relaxation necessitates meas- [ JPldt ImmHg/,
urement of at least three vari- 6000
ables (Table 2): timing (systolic
duration), relaxation rate, and
relaxation rate pattern (eg, phase
plane). [Modified from Brutsaert
and Sys (23); with permission.]
o f. /" 2oog~.__. -6000 W

-6000
i/Vm

bradycardic therapy or procedures that shorten systolic
duration, such as pressure or volume unloading of the
ventricle, are then the obvious treatments of choice.
I m p a i r e d Relaxation. In contrast to prolonged con-
traction (or delayed or retarded relaxation), the primary
event of impaired relaxation (or slowed or incomplete
relaxation) is an inappropriate reduction in rate or in the
extent of relaxation during pressure decline or early
rapid filling (Fig. 2, right). As a consequence, the relax-
ation process extends late into diastole, resulting in an
upward shift of the diastolic pressure-volume relation,
thus leading to diastolic failure.
Given the numerous limitations of relaxation rate meas-
urements as outlined above, one could, however, wonder
what transforms a given appropriate change in rate into
an inappropriate one. An additional problem is that
impaired relaxation can be observed in conditions where
systolic duration is prolonged as, for example, in phase II
of pressure-volume overloading (Fig. 8, middle), as well
as in conditions where it is abbreviated such as ischemic
heart disease (61) or in the presence of systolic failure
(Fig. 8, right). Theoretically, only when for any given
systolic duration and heart rate relaxation rate has been
reduced to such a degree that it leads to an upward shift
of the diastolic pressure-volume relation, can it be con-
sidered as a manifestation of impaired relaxation. For rate
measurements to be of practical use in the diagnosis of
diastolic dysfunction or pending diastolic failure, one
should first know the normal range of relaxation rate
measurements after normalization for systolic duration
and heart rate. This inventory must still be made.
Causes of impaired systolic relaxation include (1)
diminished myocardial load dependence due to im-
paired inactivation (Ca z handling, detachment of cross
bridges, affinity of the contractile proteins, etc) (62); (2)
excessive increases in load; and (3) inappropriately
increased nonuniformity of load and inactivation in time
and space (2,16).
232 Journal of Cardiac Failure Vol. 3 No. 3 September 1997
./,-'-
p /
/ ',
,""-, \
17
time
Fig. 6. Prolongation of pressure-generating capacity during
ejection: a combination of cooperative activity and late ejec-
tion unloading. Isovolumic left ventricular pressure (P) wave-
forms (dotted lines), from first beats after isovolumic clamps
at different times during filling, illustrate volume dependence
of systolic duration; corresponding volume (V) traces are in
the lower panel. Full lines represent the steady-state ejecting
beat, which starts (isovolumic contraction) and ends (end-dias-
tole) at the highest volume of the clamped beats. On the one
hand, pressure generation of the ejecting beat is prolonged
when referred to the isovolumic beat at the smaller volume.
This may result from the interaction of two simultaneously
occurring events: contraction load is higher through higher ini-
tial pressure and volume, hence promoting cooperative activity
at the crossbridge level, and relaxation load is decreasing dur-
ing late ejection as a result of the pressure reversal at this
instant created by the momentum. On the other hand, pressure
generation of the ejecting beat is abbreviated when referred to
the higher volume isovolumic beat: contraction load is pro-
gressively decreased through unloading during early ejection,
hence gradually diminishing the effect of cooperative activity
of the crossbridges. As a result, the timing of relaxation in
the ejecting beat is intermediate between relaxations in the
smaller- and the higher-volume isovolumic beats. The auxo-
tonic nature of the filling period is illustrated by the initial
pressure decline and later pressure rise during the volume
increase in the ejecting beat. [Pressure traces modified from
Burkhoff et al. (25) with permission; volume traces schemati-
cally reconstructed.]
Decreased Myocardial or
Ventricular Compliance
A decrease in myocardial or ventricular diastolic com-
p l i a n c e - o r an increase in diastolic stiffness--may lead
to an inappropriate upward shift of the diastolic portion
of the ventricular pressure-volume relation and, hence,
to diastolic dysfunction and failure. As a convenient way
to measure ventricular compliance/stiffness, many inves-
tigators display pressure-volume (or pressure-dimen-
sion) loops obtained from single cardiac beats. In the
ventricular filling portion of these single-beat loops one
cannot possibly distinguish, however, between early
rapid filling (usually about 80-85% of the volume
change) and true diastole, that is, diastasis and the atrial
contraction phase. Hence in such an approach, late sys-
tolic abnormalities during ventricular relaxation cannot
possibly be differentiated from decreased diastolic com-
pliance as a cause of diastolic heart failure. This is one
example, among numerous others, emphasizing the need
for a more rigorous definition of diastole as discussed
above.
In a most elegant experimental study, Pak et al. raised
some serious concern regarding the traditional analysis of
chamber stiffness based on single steady-state beats (63).
Figure 9A, B illustrates pressure-volume loops ob-
tained from patients with hypertrophic cardiomyopathy
(A) and from normal control patients (B) (63). For com-
parison, two different methods to estimate LV pres-
sure-volume relations were superimposed: (1) pres-
sure-volume relations obtained from single steady-state
beats and (2) pressure-volume relations obtained from
multiple beats during a transient preload reduction by
caval occlusion. In the former viscoelastic single-beat
loops, stiffness data were derived in a dynamic fashion
during the entire filling (hence, erroneously, including
early rapid filling during ventricular relaxation), whereas
in the latter multiple-beat method a monoexponential fit
was constructed from genuine diastolic data points. With
the latter method, a pressure-volume relation was recon-
stituted devoid of possible interference from impaired
systolic relaxation during early rapid ventricular filling.
Here, diastole has obviously been considered more cor-
rectly in the stricter conceptual sense of the heart as a
muscular pump as defined by us (Fig. 1). The disparity
between the two estimates was striking. When derived
from (end-)diastolic pressure-volume data points from
multiple beats, diastolic chamber stiffness in the hyper-
trophic cardiomyopathy was more concordant with data
from the control patient: the single-beat analysis erro-
neously makes the diastolic pressure-volume relation
appear much more compliant than the multiple-beat
method. Although the authors claim that the reason for
this disparity is still unclear, it raises at least some seri-
ous concern regarding measurements of chamber stiff-
 Diastolic Dysfunction in Heart Failure Brutsaertand Sys 233

ltCLIJ IIRLJJ
Fig. 7. Summary of published
IIMPEDANCE] IMOMENTUMI
/.~-~ ~ refleeted waves
effects of increased contraction
and relaxation loadings on left / i"~ ~ ~ 1 restrfngfrces~"lnternal
ventricular systolic duration and
left ventricular relaxation rates.
(untwisting)
Pressure (P)-, volume (V)-, and
/ ~\ ~ ICORONARYENGORQEMENTI
mitral flow (F)-versus-time (t) / ',\ \
traces (top) illustrate the approxi- IP.E,o l] ', IA P.ESSUREI
mate time sequence of impact of " . , ~
various contraction (CL) and

2/"
relaxation (RL) loadings. The
effects on systolic duration are
consistent prolongation (O) for
increased CL and abbreviation
(O) for increased relaxation
loading (bottom). For increased I ~ I A i r~
impedance as a RL, see also
Fig. 5 (bottom). For increased
F ~!, ' .... t
momentum as a relaxation
unloading, see also Fig. 6. The
effects of increased loading on
measurements of relaxation rate
(dP/dt-, tau, dV/dt, E) are vari- INCREASED SYSTOLIC RELAXATION
able (+, increased rate; -, LOADING DURATION RATES
decreased rate; 0, unchanged
rate) and depend not only on the dP/dt (-) T~ u dV/dt E
change in systolic duration but
also on the experimental condi- l CONTRACTION LOAD (CL)
Preload 4--t-4- 0 O+ 4-
tion. With changes in loading,
measurements of systolic dura- Afterload 4-+4- + O- O+ + 0--
tion seem to be more reliable
than relaxation rates to evaluate RELAXATION LOAD (RL)
late systolic cardiac performance. Impedance O+ _
RT or Rt, right; LT or Lt, left. Momentum -I-+ +

Configuration
Rt-Lt Interaction 7 4- N

Coronary Engorgement 7 -- 4-

Wall tension at MO 7 - (7)

Atrial Pressure 7 + +

ness based on a viscoelastic model using single beats and
which includes the entire early rapid filling phase of
(systolic) ventricular relaxation. Accounting for a mis-
match in the systolic-to-total duration could perhaps help
to clarify this enigma. Indeed, systolic duration is usu-
ally significantly prolonged in nonfailing hypertrophic
cardiomyopathy at baseline, independently of the con-
comitant impaired relaxation, and would be substantially
abbreviated by preload reduction. As emphasized by the
authors, even in the normal control heart (Fig. 9B), there
was a slight disparity between the two models. Similar
observations were made after vena caval occlusion in
conscious dogs with tachycardia-induced dilated car-
diomyopathy (65).
Another example of the erroneous pitfall introduced
by the traditional use of single-beat pressure-volume
loops is also illustrated in Figure 9 C, D (64). Here, pres-
sure-volume loops were displayed at increasing heart
rates during cardiac pacing in patients with coronary
artery disease (C) and normal control patients (D). The
downward shift in the dynamic viscoelastic loop in the
normal control patients at the higher rates suggested
234 Journal of Cardiac Failure Vol. 3 No. 3 September 1997

IP SE 'I IP SE Ill [PHASE IIIl

SYSTOLIC COMPENSATION SYSTOLIC COMPENSATION DIASTOLIC and SYSTOLIC
prolonged contraction or with DIASTOLIC FAILURE FAILURE
p delayed/retarded relaxation loss of compensatory
prolon ted contraction
..,..=...o% g

balanced systolic-to-total duration
IAims for Treatment I
remove P-V overloading
I,~ tachycardia I
~1 I
mismatched systolic-to-total duration mismatched systolic-to-total duration
impaired relaxation impaired relaxation
decreased diastolic compliance decreased diastolic compliance
[Aims for Treatment] [Aims for Treatment]
bradycardic agents treatment of systolic failure
e.g. beta-blockade e.g, ACE-Inhibitors
abbreviation of systole by gentle = bradycardic agents
preload/aftedoad reduction e.g. low dosage beta-blockade
e.g, . nitrc-derivatives (digitalis)
diuretics prolongation of systole and
ACE-Inhibitors acceleration of relaxation
Ca~-channel blockers e.g. , Ca'-sensitizers (?)
acceleration of relaxation cardiac endothelial protection (?)
e.g. beta-agonists

Fig. 8. Pathophysiologic evolution of pressure and/or volume overloading. The successive phases of the pathophysiologic evolution
of pressure and/or volume overloading of the left ventricle are illustrated by pressure (P)-versus-time (t) curves (dotted lines), in com-
parison with the baseline pressure curve (full lines) prior to overloading. Phase I is characterized by systolic compensatory prolonga-
tion. Phase II, systolic compensation with diastolic failure, is reached when a mismatch of systolic-to-total duration results from
impaired relaxation, decreased compliance, or inappropriately high heart rate: the diastolic pressure-volume relation will shift
upward and result in exercise intolerance. Finally, phase III is characterized by the simultaneous failure of both systolic and diastolic
performance. The aims of treatment in the different phases are a logical consequence of the analysis. ACE, angiotensin-converting
enzyme. [Modified from Brutsaert et al. (2), with permission.]

decreased ventricular stiffness, whereas a (more appro- Measurements and Indices of LV

priate) monoexponential fit of the (end-)diastolic data
points (solid dots) did not reveal such changes. Incorpo-
ration of variations in the systolic-to-total duration could
perhaps again help to clarify the disparity. By contrast in
patients with coronary artery disease, there was a clear
upward shift of the (end-)diastolic data points at higher
heart rates, reflecting, as expected, increased diastolic
stiffness.
Figure 10 (66-69,119) illustrates that similarly, in var-
ious physiologic conditions as, for example, during
interventions that act either through homeometric (70)
(Fig. 10A) or through cardiac endothelial (Fig. 10B)
autoregulation, care needs to be exercised in the interpre-
tation of single-beat diastolic pressure-volume relations.
The disparity of single- versus multiple-beat diastolic
pressure-volume relations in all these conditions may
again result from alterations in the systolic-to-total dura-
tion in the presence of unaltered genuine diastolic pres-
sure-volume relations.
Diastolic Dysfunction and Failure
As discussed above, the diagnosis of diastolic dys-
function or failure relies on the observation of an inap-
propriate upward shift of the (end-)diastolic pressure-
volume relation or inappropriate increase of any directly
related measurement, such as pulmonary capillary
wedge pressure and A wave on the apex cardiogram and,
more indirectly, transmitrai Doppler A-to-E wave ratio,
during exercise (diastolic dysfunction) or at rest (dias-
tolic failure). As will be outlined below, correct manage-
ment, however, relies on a precise knowledge of the
exact cause of such shifts, that is, inappropriate tachycar-
dia, or decreased compliance, or impaired relaxation, or
a combination.
Evaluation of these causes consists of assessment of
(1) systolic relaxation during LV pressure fall and early
rapid filling, that is, measurement of systolic duration, of
peak relaxation rates normalized for systolic duration, of
 Diastolic Dysfunction in Heart Failure * Brutsaert and Sys 235

i i

CAD
3O

II HCM 40

i
i,o i
.2O I ~ . J
i
I

100/min
e~
I--~ caval I0
.e
occlusion 85/min

t t f 40 SO
0 2O
A ~S SO 7S 10O C
30

I I t l[I I

CONTROL 40
i
CONTROL
E P 30
I

20
, :
10
IQ , r

0 i
2S 5O 7S 100 t25 80

B Volume (ml) D
v ~ (~1
Fig. 9. Diastolic dysfunction or failure and myocardial and ventricular compliance: single- versus multiple-beat analysis. (A, B)
Comparison of left ventricular pressure-volume relations as derived from single-beat steady-state data (filled circles) or from end-
diastolic data from multiple beats during preload reduction (open triangles). Despite reasonable concordance of both methods in a
control patient (B), the single-beat method erroneously makes the diastolic pressure-volume relation appear markedly more compli-
ant than the multiple-beat method in a patient with hypertrophic cardiomyopathy (A). (C, D) Comparison of left ventricular pres-
sure-volume relations at increasing heart rates. Single-beat steady-state data show almost unchanged slope of the pressure-volume
relation during filling, although at higher heart rates, filling occurs at higher pressures in a control patient and at lower pressures in a
patient with coronary artery disease (CAD). Only in CAD do the true end-diastolic data points (filled circles), as expected, reflect an
increased diastolic chamber stiffness. [A, B modified from Pak et al. (63) and C, D modified from Grossman (64), with pemaission.]

relaxation rate patterns, etc. (Table 2), and (2) multiple-
beat diastolic pressure-volume and stress-strain rela-
tions of the myocardium (Figs. 9, 10). These can be per-
formed from high-fidelity LV pressure recordings and
simultaneous high-speed LV angiograms. In addition,
through the wide application of powerful noninvasive
techniques there has been increasing understanding of
abnormal LV filling patterns and transmitral flow profiles
during systolic LV relaxation. From these noninvasive
techniques, in particular, echo-Doppler and radionuclide
imaging, numerous indices have been derived (71-83).
Since the worldwide application of Doppler echocardio-
graphy and radionuclide imaging, LV relaxation rate and
interval measurements have become easily accessible. It
has been tantalizing to speculate (15) that a single abnor-
mal index can be used to identify patients with relaxation
abnormalities. It is often forgotten, however, that these,
mainly rate, measurements are only indirect measures of
LV function providing no direct assessment of systolic
LV relaxation or of diastolic compliance. Moreover, non-
invasive measurements of LV systolic relaxation rates
during pressure fall and early filling (isovolumic re-
laxation time, Doppler E wave, dV/dt, time to peak fill-
ing rate, etc) without considerations of overall systolic
duration have contributed significantly to the many
diagnostic misinterpretations of systolic-versus-dias-
tolic dysfunction and failure. In the absence of a dispro-
portionally increased ventricular diastolic pressure at
(end-)diastolic volume or of derived indices, these non-
invasive rate measurements should be interpreted with
caution (50,84-87). Several excellent reviews have been
published recently warning against uncritical applica-
tion of these techniques as the sole basis for diagnosis
and therapy (50,52,59,71,84).
An approach frequently used by clinicians is the
attempt to resolve scientific questions by searching for
236 Journal of Cardiac FailureVol.3 No. 3 September 1997

'[ DOBLITAMINE E X D E R C I S E rt B L O C K E D
~.xe m...ise

E
~'~ 101) B0 L . I :

'i ',,,

13-
> L / "~,
...J ~ i Z
0 [

I i t
2~ 36 52 50 65
A Volume(ml) Volume(ml) Volume (m[)

.o! 5V=118ml

- CONTROL D - ~OL
120- i ~ ' '
, ~ ~ J substance P [. . . . .
: I
I
E It/I "4,:, 1i
I C.~trol
s0~ ,
I
[ NO 0
tMO=TZ/ 2
['3 .,an. "

- :oo "i
o 2o 40 6o ~o ]oo ~ o ~4o J6o I eo I F6o I o

B Volume(ml) Volume(ml) Dimension (era)

Fig. 10. (A) Homeometric and (B) cardiac endothelial control of diastolic pressure-volume relation. (A) Left ventricular (LV) pres-
sure-volume loops at rest and during exercise, in control and after dobutamine, and at rest and during exercise under beta blockade
were obtained from averaged data during a 15-second recording. Changes in ventricular stiffness, or the absence of such changes,
should be derived from the true end-diastolic data points (filled circles). The present examples illustrate that such changes cannot cor-
rectly be derived from the single-beat viscoelastic approach, because it takes the pressure-volume relation during the entire filling
period into account. (B) In the pressure-volume loops (left) obtained before (control) and at the end of a bicoronary infusion of sub-
stance P in a healthy subject, single- and multiple-beat methods are concordant in suggesting an increased compliance of the ventri-
cle under substance R Nitroprusside (open symbols in middle and right) consistently decreases the pressure at similar volumes or
dimensions in the smaller volume range during the filling period. Yet, one could imagine one and the same pressure-volume or
-dimension curve for each patient to fit the true end-diastolic pressure-volume or -dimension points for the control data (closed sym-
bols) and the nitroprusside data together, hence unchanged diastolic chamber stiffness. SV, stroke volume; HR, heart rate. [A Modi-
fied from Cheng et al. (66), B (left) from Paulus (119), B [middle] modified from Smith et al. (68), and B (right) modified from Car-
roll et al. (69), with permission.]

correlations between often widely unrelated parameters. problems and theoretical limitations (90). In addition and
Apart from considerations about the doubtful scientific apart from the inherent circular argument hidden in this
basis for deriving concepts from such correlations, it can approach, this relationship lacks a conceptual basis and
be anticipated that, when applied to medicine, the more it overlooks the substantial shifts in the instant at which
advanced a disease state the higher such correlations will peak systolic pressure and tan are measured when the
be. One example of such circular reasoning is the recent amplitude of peak systolic pressure is experimentally
introduction of tan versus ventricular afterload (end- or altered to obtain this relationship. Normalization of tau
peak systolic pressure or force) for the evaluation of ven- or of peak pressure for baseline or for peak isovolumic
tricular performance (32,33,65). This approach was pressure, respectively (42), eclipses these manipulations
derived from the excellent work of Gaasch and co-work- of data even more. Moreover, experimental data have
ers on the various determinants of myocardial relaxation disproved that it would constitute a load independent
in vivo (88,89). assessment of cardiac performance (51).
In a most elegant editorial, Little criticized this In this regard, we remind the reader that since the
approach when uncritically applied as a diagnostic tool, early 1970s, there has been general agreement that in the
emphasizing that it is fraught with numerous technical evaluation of systolic ventricular performance during the
 Diastolic Dysfunction in Heart Failure
Table 2. Indices of Left Ventricular (LV) Systolic Relaxation
as Derived From LV Pressure Measurements, Doppler
Echocardiography, and Radionuclide Angiography*
Measurements of LV systolic duration (systolic time intervals)
Time from onset (R wave on electrocardiogram)(ms)
To opening of aortic valve (PEP or ICT)
To closing of aortic valve (PEP + LVET)
To peak dP/dt(-)
To 10% LVP decline
To 90% LVP decline
To onset dV/dt(+)
To peak dV/dt(+)
To onset doppler E-wave
To peak doppler E-wave
LV systolic-to-total(R-R interval) duration
LV filling period-to-total(R-R interval) duration
Measurements of LV systolic relaxation rate
LVP fall:
Peak dP/dt(-) (mmHg/s)
Peak dS/dt(-) (g/cm2/s)(LVwall stress)
Isovolumicrelaxation time (interval between aortic valve closure
and mitral valve opening, IVRT) (ms)
Time constant (tau) of LV isovolumicP fall (ms)
Phase plane dP/dt(-) vs LVP (mmHg/s vs mmHg)
LV filling (early rapid):
Peak dV/dt(+)
Time from OnsetdV/dt(+) to peak dV/dt(+) (ms)
Peak Doppler E wave (cm/s)
E-wave deceleration time (DT) (ms)
Time from onset E wave to peak E wave (ms)
Peak filling rate (E wave x mitral valve area)
Normalized peak filling rate (peak filling rate/LV end-diastolic
volume ratio)
Duration of E wave (ms)
E-wave velocity-time integral (VTI) (cm)
* Note that all systolic time intervals should be measured from the
onset of the cardiac cycle (R wave on electrocardiogram).
LVE left ventricular pressure; ICT, isovolumic contraction time;
LVET, left ventricular ejection time; PEP, preejection period.
contraction phase, considerations of time could for prac-
t i c a l - t h o u g h thermodynamically incorrect--reasons be
discarded, the argument being that myocardial activation
(activating Ca 2+, affinity of the contractile proteins, num-
ber of crossbridges, cooperative activity) is sufficiently
high during the larger portion of this phase. Eliminating
time did allow for evaluation of myocardial contractility
or of ventricular performance during contraction based
on an analysis of the time-independent force-velocity-
length interrelation (91) or of corresponding measure-
ments or derived indices at the ventricular level; during
the contraction phase, this approach is still valid up to
the present. Hence, in combination with pressure and
volume, rate measurements continue to be of practical
use in the evaluation of ventricular performance during
the contraction phase, that is, during LV pressure rise
and ejection.
By contrast, investigations during the past two decades
on ventricular relaxation during isovolumic pressure fall
and rapid filling have revealed that considerations of time
and loading are inherent to the process of inactivation
Brutsaert and Sys 237
during relaxation. Decline in activating Ca 2+, detachment
of crossbridges, changes in the affinity in the contractile
proteins, reversed cooperative activity, and so on are all
dynamic processes returning to a state of minimal
entropy in diastole (16). During this vulnerable and ther-
modynamically highly unstable transient toward a state of
nonequilibrium with reduced entropy, both time and load-
ing (load dependence of relaxation) are critical determi-
nants of these processes. Given, moreover, the substantial
variations in the systolic-to-total duration ratio resulting
from shifts in time of relaxation as shown above with
changes in load, drugs, and cardiac endothelium, timing
and normalization for these time shifts are essential in
any analysis of ventricular relaxation. Hence, searching
for a load- and/or time-independent measure during this
phase is like "noyer le poisson."
Implications for Therapy
There is general consensus that diastolic dysfunction
and diastolic failure can be treated (1,5,92,93). First,
causes or aggravating conditions, such as coronary artery
disease and pressure and/or volume overloading, should
be corrected if possible. Hence, myocardial ischemia
and/or hypertrophy should be prevented or reduced by
appropriate therapeutic interventions (94-98); however,
apart from this causal therapeutic strategy and apart from
some general recommendations common to both dias-
tolic and systolic failure, there are important differences
in the pharmacologic management of diastolic versus
systolic dysfunction and failure.
Although there is no specific therapy for diastolic dys-
function and failure, the goal should be to normalize dias-
tolic pressure-volume relations and to relieve symptoms
of pulmonary congestion and exercise intolerance, that is,
exercise-induced dyspnea. On theoretical grounds, one
should take into account the above three major subgroups
of pathophysiologic causes. From these, at least three
subclasses of medication can be derived.
First, when an inappropriate increase in heart rate par-
ticipates in causing symptoms of pulmonary congestion
or exercise intolerance (ie, exercise-induced dyspnea),
low dosage of a beta blocking agent is the treatment of
choice (99). Drugs with selective bradycardic properties
and devoid of (positive or negative) inotropic properties
have been commercialized, but compared with low-
dosage beta blockade, with very little success. Apart from
a reduction in heart rate and stabilization of rhythm, beta
blockade has the additional beneficial effects of protect-
ing the myocardium against the harmful effects of sym-
pathetic overactivity and, possibly, improving myocardial
energetics and remodeling the left ventricle.
Second, increasing attention has been given to devel-
oping drugs aimed at improving the passive properties of
the myocardium, for example, either by suppressing
inappropriate growth of noncontractile tissue c o m p o -
238 Journal of Cardiac Failure Vol. 3 No. 3 September 1997
nents or by helping to regress myocardial hypertrophy.
Examples of this class of remodeling drugs are angio-
tensin-converting enzyme (ACE) inhibitors and antial-
dosterone agents (eg, spironolactone). In contrast to the
plethora of studies in animals (100-102), studies
demonstrating the effectiveness of such drugs in
patients with diastolic dysfunction or failure are, how-
ever, limited (92,103-107). In view of the above con-
siderations on single-beat pressure-volume relations
(Figs. 9, 10), it may be of interest to note that in some
very specific conditions, such as hypertrophic car-
diomyopathy (Fig. 9A, B), mere unloading of the heart
may lead more efficiently to a drastic reduction of con-
gestion, albeit by allowing the operating position of the
single-beat pressure-volume relation during the early
major filling portion of the curve to descend along an
unaltered passive diastolic pressure-volume curve, hence
allowing early rapid filling to occur at lower filling pres-
sures in the presence of unchanged diastolic compliance.
Similar observations but in different clinical conditions
were made with nitro derivatives (Fig. 10B). To what
extent such therapeutic improvements (1,93,107-112)
result from normalization of the systolic-to-total dura-
tion (Fig. 8, middle) requires further investigation.
Third, most efforts have been directed at developing so-
called lusitropic* drugs, that is, drugs aimed at improving
impaired relaxation. The problem with this category of
drugs is that only a few studies have examined their action
on diastolic pressure-volume relations. Most of these
studies have evaluated drag efficacy by merely analyzing
relaxation rate measurements, but in none of these studies
have considerations about systolic duration been taken
into account. The former approach, measurements of
relaxation rates, has been summarized in an excellent
review (113) for various classes of drugs and for various
categories of disease states that lead to diastolic failure. In
view of the above, however, whether and to what extent a
drug would be positive lusitropic depend only on the
degree to which such a drug can improve the diastolic
pressure-volume relations in so far as impaired systolic
relaxation had been the cause of the upward shift. In other
words, whether a drug is positive lusitropic does not
depend on the nature of the molecule but on its action in
any given disease and, in particular, on the phase during
the pathogenesis of the disease. For example, in a broader
context of conditions with pressure or volume overloading
(Fig. 8), positive lusitropic drugs would be drugs that
either abbreviate systolic duration and/or augment relax-
ation rate whenever there is a mismatch of the systolic-to-
total duration with impaired (ie, slowed or incomplete)
relaxation (Fig. 8, left and middle) or, on the other hand,
prolong systolic duration but also fasten relaxation when-
ever diastolic dysfunction or failure is accompanied by
systolic failure (Fig. 8, right). Hence, when merely refer-
ring to relaxation rate, the terms positive lusitropy and
negative lusitropy should be avoided. Even more cumber-
some is the still unresolved question whether treating
mere abnormalities in LV systolic relaxation rates during
LV pressure fall or early rapid filling, when these do not
lead to an inappropriate rise in the diastolic pressure-vol-
ume relations and, hence, when these do not cause dias-
tolic dysfunction or failure as defined here, would be ben-
eficial to the patient.
The above considerations should also be kept in mind
whenever new therapeutic strategies (114-118) such
as cardiac endothelial protection, calcium-sensitizing
drugs, atrial or brain natriuretic peptides, and potassium
channel drugs are developed.
Conclusion
Despite the profusion of publications on diastolic dys-
function and diastolic failure in the presence of normal
systolic ventricular function, the diagnosis, prevalence,
prognosis, and management of these conditions remain
largely unknown, the main reason being the lack of
appropriate definitions of diastolic function, dysfunction,
and failure. This lack of consensus among clinicians has
been reinforced by the easy access to powerful noninva-
sire techniques in cardiology. In this review, we took a
conceptual approach. Considering the heart as a muscu-
lar pump, we discussed the pathophysiology of ventricu-
lar relaxation and filling. In addition, we derived a patho-
physiologically unquestionable and at the same time
clinically useful definition of diastolic dysfunction and
failure. With this definition in mind and taking into
account stricter criteria for normal systolic performance,
we feel that the previously presumed clinical prevalence,
prognosis, and treatment of primary diastolic heart fail-
ure should be reconsidered.
*Lusitropic (16): The term lusitropic was coined by Phylis B. Katz
(A. M. Katz, personal communication)to mean predominantly acting
(positively or negatively) on relaxation of the heart both as muscle and
as pump. Lusitropic and lusitropy are from the Greek words lusis
meaning loosening, releasing, ransoming, means of letting, deliver-
ance from guilt, redemption of mortgage or pledge, emptying, evacua-
tion, emission of semen, unraveling, softening, or divorce" and tropos
meaning "turn, direction, way, manner, or fashion."
The major advantage of the term lusitropic is its potential useful-
ness as a general term to describe interventions that preferentially act
on relaxation. Unfortunately,it suffers from the fact that it lacks suffi-
cient specificity as for the different phases to which the term is meant
to relate during relaxation. It is also not clear what positive or negative
lusitrnpy means. Do these connotations refer to changes in onset, in
speed, or in extent, or do they, instead, refer to changes in the time pat-
tern of relaxation with little changes in onset, peak speed, and/or
extent? Do they refer to inactivation or do they also incorporate effects
mediated through changes in loading. For all these reasons and despite
the beauty of the term, it has been suggestedby many that it should not
be used any longer.
 Diastolic Dysfunction in Heart Failure
References
1. Cohn JN, Johnson G: Veterans Administration Cooperative
Study Group: Heart failure with normal ejection fraction:
the V-HeFT study. Circulation 1990;81 :III-48-53
2. Brutsaert DL, Sys SU, Gillebert TC: Diastolic failure:
pathophysiology and therapeutic implications. J Am Coll
Cardiol 1993;22:318-25
3. Lenihan DJ, Gerson MC, Hoit BD, Walsh RA: Mecha-
nisms, diagnosis, and treatment of diastolic heart failure.
Am Heart J 1995;130:153-66
4. Vasan RS, Benjamin EJ, Levy D: Congestive heart failure
with normal left ventricular systolic function. Arch Intern
Med 1996;156:146-57
5. Ritchie JL, Cheitlin MD, Eagle KA, Gardner TJ, Garson
A, Gibbons RJ, Lewis RR O'Rourke RA, Ryan TJ: Guide-
lines for the evaluation and management of heart failure:
ACC/AHA Task Force Report. J Am Coll Cardiol
1995;26:1376-98
6. Tresch DD, McGough MF: Heart failure with normal sys-
tolic function: a common disorder in older people. J Am
Geriatr Soc 1995;43:1035-42
7. Vasan RS, Benjamin EJ, Levy D: Prevalence, clinical fea-
tures and prognosis of diastolic heart failure: an epidemio-
logic perspective. J Am Coil Cardiol 1995;26:1565-74
8. Packer M: Abnormalities of diastolic function as a poten-
tial cause of exercise intolerance in chronic heart failure.
Circulation 1990;81 :III-78-86
9. Schaufelberger M, Andersson G, Eriksson BO, Grimby G,
Held R Swedberg K: Skeletal muscle changes in patients
with chronic heart failure before and after treatment with
enalapril. Eur Heart J 1996;17:1678-85
10. Coats AJS: Heart failure patients: why do they fatigue,
how do they get better? Eur Heart J 1996;17:1615-17
11. Opasich C, Aquilani R, Dossena M, Foppa R Catapano
M, Pagani S, Pasini E, Ferrari R, Tavazzi L, Pastoris O:
Biochemical analysis of muscle biopsy in overnight fast-
ing patients with severe chronic heart failure. Eur Heart J
1996; 17:1686-93
12. Goldsmith SR, Dick C: Differentiating systolic from
diastolic heart failure: pathophysiologic and therapeutic
considerations. Am J Med 1993 ;95:645-55
13. Brogan III WC, Hillis LD, Flores ED, Lange RA: The
natural history of isolated left ventricular diastolic dys-
function. Am J Med 1992;92:627-30
14. Pernenkil R, Vinson JM, Shah AS, Beckham V, Witten-
berg C, Rich MW: Course and prognosis in patients > 70
years of age with congestive heart failure and normal ver-
sus abnormal left ventricular ejection fraction. Am J Car-
diol 1997;79:216-9
15. Lew WYW: Evaluation of left ventricular diastolic func-
tion. Circulation 1989;79:1393-7
16. Brutsaert DL, Sys SU: Relaxation and diastole of the
heart. Physiol Rev 1989;69:1228-1315
17. Kitzman DW, Higginbotham MB, Cobb FR, Sheikh KH,
Sullivan MJ: Exercise intolerance in patients with heart
failure and preserved left ventricular systolic function:
failure of the Frank-Starling mechanism. J Am Coll Car-
diol 1991;17:1065-72
Brutsaert and Sys 239
18. Grossman W, Lorell BH: Diastolic relaxation of the heart.
Kluwer Academic, Boston, 1994
19. Brutsaert DL, Rademakers FE, Sys SU: Triple control of
relaxation: implications for the cardiac patient. Circula-
tion 1984;69:190-96
20. Slinker BK, Shroff SG, Kirkpatrick RD, Campbell KB:
Left ventricular function depends on previous beat ejec-
tion but not previous beat pressure load. Circ Res
1991;69:1051-7
21. Gillebert TC, Brutsaert DL: Regulation of left ventricular
pressure fall. Eur Heart J 1990; 11:124-32
22. Brutsaert DL, Housmans PR, Goethals MA: Dual control
of relaxation: its role in the ventricular function in the
mammalian heart. Circ Res 1980;47:637-52
23. Brutsaert DL, Sys SU: Systolic and diastolic heart func-
tion. J Cardiovasc Pharmacol 1996;28:SI-8
24. Hunter WC: End-systolic pressure as a balance between
opposing effects of ejection. Circ Res 1989;64:265-75
25. Burkhoff D, De Tombe PR Hunter WC: Impact of ejec-
tion on magnitude and time course of ventricular pres-
sure-generating capacity. Am J Physiol 1993;265(Heart
Circ Physiol 34):H899-909
26. Noble MIM: The contribution of blood momentum to left
ventricular ejection in the dog. Circ Res 1968;23:663-70
27. Pouleur H, Lefevre J, Van Mechelen H, Charlier AA:
Free-wall shortening and relaxation during ejection in the
canine right ventricle. Am J Physiol 1980;239(Heart Circ
Physiol):H601-13
28. Varma SK, Owen RM, Smucker ML, Feldman MD: Is T
a preload-independent measure of isovolumetric relax-
ation? Circulation 1989;80:1757-65
29. Gaasch WH, Carroll JD, Blaustein AS, Bing OHL:
Myocardial relaxation: effects of preload on the time
course of isovolumetric relaxation. Circulation 1986;
73:1037-41
30. Karliner JS, LeWinter MM, Mahler F, Engler R,
O'Rourke RA: Pharmacologic and hemodynamic influ-
ences on the rate of isovolumetric left ventricle relaxation
in the normal conscious dog. J Clin Invest 1977;60:
511-21
31. Tobias AH, Slinker BK, Kirkpatrick RD, Campbell KB:
Mechanical determinants of left ventricular relaxation in
isovolumically beating hearts. Am J Physiol 1995;268
(Heart Circ Physiol 37):H170-77
32. Su JB, Hittinger L, Laplace M, Crozatier B: Loading
determinants of isovolumic pressure fall in closed-chest
dogs. Am J Physiol 1991;260(Heart Circ Physiol 29):
H690-7
33. Eichhorn EJ, Willard JE, Alvarez L, Kim AS, Glamann
DB, Risser RC, Grayburn PA: Are contraction and relax-
ation coupled in patients with and without congestive
heart failure? Circulation 1992;85:2132-9
34. Campbell KB, Kirkpatrick RD, Knowlen GG, Ringo JA:
Late-systolic pumping properties of the left ventricle:
deviation from elastance-resistance behavior. Circ Res
1990;66:218-33
35. Sch~ifer S, Fiedler VB, ThSmer V: Afterload dependent
prolongation of left ventricular relaxation: importance of
asynchrony. Cardiovasc Res 1992;26:631-37
240 Journal of Cardiac Failure Vol. 3 No. 3 September 1997
36. Garrido JM, Gerson MC, Holt BD, Walsh RA: Load
independence of early diastolic filling parameters in the
anesthetized canine model. J Nucl Med 1993;34:1520-8
37. Raft GL, Glantz SA: Volume loading slows left ventricu-
lar isovolumic relaxation rate: evidence of load-depen-
dent relaxations in the intact dog heart. Circ Res 1981;
48:813-24
38. Zile MR, Gaasch WH: Load-dependent left ventricular
relaxation in conscious dogs. Am J Physiol 1991;261
(Heart Circ Physiol 30):H691-9
39. Kohno M, Katayama K, Fujii T, Yano M, Ogawa H, Mat-
suda Y: The change of magnitude of arterial wave reflec-
tion affects the left ventricular relaxation. Circulation
1990;82:III-121
40. Nikolic S, Yellin EL, Tamura K, Tamura T, Frater RWM:
Effect of early diastolic loading on myocardial relaxation
in the intact canine left ventricle. Circ Res 1990;66:
1217-26
41. Hofi M, Inoue M, Kitakaze M, Tsujioka K, Ishida Y, Fuku-
nami M, Nakajima S, Kitabatake A, Abe H: Ejection timing
as a major determinant of left ventricular relaxation rate in
isolated perfused canine heart. Circ Res 1984;55:31-8
42. Gillebert TC, Leite-Moreira AE De Hert SG: Relax-
ation-systolic pressure relation: a load-independent
assessment of left ventricular contractility. Circulation
1997;95:745-52
43. Stoddard MF, Pearson AC, Kern MJ, Ratcliff J, Mrosek
DG, Labovitz AJ: Influence of alteration in preload on the
pattern of left ventricular diastolic filling as assessed by
Doppler echocardiography in humans. Circulation 1989;
79:1226-36
44. Choong CY, Herrmann HC, Weyman AE, Fifer MA: Pre-
load dependence of Doppler-derived indexes of left ven-
tricular diastolic function in humans. J Am Coll Cardiol
1987;10:800-8
45. Bahler RC, Martin P: Effects of loading conditions and
inotropic state on rapid filling phase of left ventricle. Am
J Physiol 1985;59:21-31
46. Courtois M, Vered Z, Barzilai B, Ricciotti NA, Perez JE,
Ludbrook PA: The transmitral pressure-flow velocity
relation: effect of abrupt preload reduction. Circulation
1988;78:1459-68
47. Gibbons-Kroeker CA, Tyberg Jg, Beyar R: Effects of
load manipulations, heart rate, and contractility on left
ventricular apical rotation: an experimental study in anes-
thetized dogs. Circulation 1995;92:130-4 1
48. Brown CD, Chow E, Farrar DJ: Left ventricular unload-
ing decreases rate of isovolumic right ventricular pressure
decline. Am J Physiol 1993;265(Heart Circ Physiol
34):H1663-9
49. Farhi ER, Canty JM, Klocke FJ: Effects of graded reduc-
tions in coronary perfusion pressure on the diastolic pres-
sure-segment length relation and the rate of isovolumic
relaxation in the resting conscious dog. Circulation
1989;80:1458-68
50. Thomas JD, Weyman AE: Echocardiographic Doppler
evaluation of left ventricular diastolic function. Circula-
tion 1991;84:977-90
51. Koiwa Y, Honda H, Takagi T, Kikuchi J, Hoshi N, Tak-
ishima T: Modification of human left ventricular relax-
ation by small-amplitude, phase-controlled mechanical
vibration on the chest wall. Circulation 1997;95:
156-62
52. Nishimura RA, Abel MD, Hatle LK, Tajik AJ: Assess-
ment of diastolic function of the heart: background and
current applications of Doppler echocardiography: Part
II: Clinical studies. Mayo Clin Proc 1989;64:181-204
53. Brutsaert DL: Nonuniformity: a physiological modulator
of contraction and relaxation of the normal heart. J Am
Coll Cardiol 1987;9:341-8
54. Park CH, Chow WH, Gibson DG: Phase differences
between left ventricular wall motion and transmittal flow
in man: evidence for involvement of ventricular restoring
forces in normal rapid filling. Int J Cardiol 1989;24:
347-54
55. Rumberger JA, Weiss RM, Feiring AJ, Stanford W, Haj-
duczok ZD, Rezal K, Marcus NL: Patterns of regional
diastolic function in the normal human left ventricle: an
ultrafast computed tomographic study. J Am Coll Cardiol
1989;14:119-26
56. Nagel E, Stuber M, Matter C, Lakatos M, Boesiger R
Hess OM: Rotational and translational motion of the
heart after myocardial infarction. J Cardiovasc Pharmacol
1996;28(suppl. 2):$31-5
57. Lew WYW, Rasmussen CL: Influence of nonuniformity
on rate of left ventricular pressure fall in the dog. Am J
Physiol 1989;256:H222-32
58. Hori M, Kirakaza M, Ishida Y, Fukunami M, Kitabatake
A, Inoue M, Kamada T, Yue DT: Delayed end ejection
increases isovolumic relaxation rate in isolated perfused
canine hearts. Circ Res 1991;68:300-8
59. Popp RL: 'High time' for noninvasive assessment of
regional ventricular diastolic ischemic dysfunction. Cir-
culation 1995;91:552-4
60. Kondo H, Masuyama T, Ishihara K, Mano T, Yamamoto
K, Naito J, Nagano R, Kishimoto S, Tanouchi J, Hori M,
Takeda H, Inoue M, Kamada T: Digital subtraction high-
frame-rate echocardiography in detecting delayed onset
of regional left ventricular relaxation in ischemic heart
disease. Circulation 1995;91:304-12
61. lhara T, Komamura K Shen YT, Patrick TA, Mirsky I,
Shannon RR Vatner SF: Left ventricular systolic dysfunc-
tion precedes diastolic dysfunction during myocardial
ischemia in conscious dogs. Am J Physiol 1994;267:
H333-43
62. Apstein CS, Morgan JP: Cellular mechanisms underlying
left ventricular diastolic dysfunction. In Gaasch WH,
LeWinter MM: Left ventricular diastolic dysfunction and
heart failure. Lea & Febiger, Philadelphia, 1994, pp. 3-24
63. Pak PH, Maughan WL, Baughman KL, Kass DA:
Marked discordance between dynamic and passive dias-
tolic pressure-volume relations in idiopathic hyper-
trophic cardiomyopathy. Circulation 1996;94:52-60
64. Grossman W: Diastolic dysfunction in congestive heart
failure. N Engl J Med 1991;325:1557-64
65. Ishizaka S, Asanoi H, Wada O, Kameyama T, Inoue H:
Loading sequence plays an important role in enhanced
load sensitivity of left ventricular relaxation in conscious
dogs with tachycardia-induced cardiomyopathy. Circula-
tion 1995;92:3560-7
 Diastolic Dysfunction in Heart Failure
66. Cheng CP, Igarashi Y, Little WC: Mechanism of aug-
mented rate of left ventricular filling during exercise. Circ
Res 1992;70:9-19
67. Paulus WJ: Paracrine coronary endothelial modulation of
diastolic left ventricular function in man: implications for
diastolic heart failure. J Cardiac Failure 1996;2(suppl.
4):$155-64
68. Smith ER, Smiseth OA, Kingma I, Manyari D, Belenkie
I, Tyberg JV: Mechanism of action of nitrates: role of
changes in venous capacitance and in the left ventricular
diastolic pressure-volume relation. Am J Med 1984;
76:14-21
69. Carroll JD, Lang RM, Neumann AL, Borow KM, Rajfer
SI: The differential effects of positive inotropic and
vasodilator therapy on diastolic properties in patients
with congestive cardiomyopathy. Circulation 1986;74:
815-25
70. Pouleur H, Karliner JS, LeWinter MM, Covell JW: Dias-
tolic viscous properties of the intact canine left ventricle.
Circ Res 1979;45:410-19
71. Little WC, Downes TR: Clinical evaluation of left ven-
tricular diastolic performance. Prog Cardiovasc Dis 1990;
32:273-90
72. Tel C, Dujardin KS, Hodge DO, Kyle RA, Tajik AJ,
Seward JB: Doppler index combining systolic and dias-
tolic myocardial performance: clinical value in cardiac
amyloidosis. J Am Coll Cardiol 1996;28:658-64
73. Cohen G1, Pietrolungo JF, Thomas JD, Klein AL: A prac-
tical guide to assessment of ventricular diastolic function
using Doppler echocardiography. J Am Coll Cardiol
1996;27:1753-60
74. Friedman B J, Plehn JF: Noninvasive analysis of ventricu-
lar diastolic performance: in quest of a clinical tool. J Am
Coll Cardiol 1988;12:944-6
75. Douglas PS, Berko B, Lesh M, Reichek N: Alterations in
diastolic function in response to progressive ventricular
hypertrophy. J Am Coll Cardiol 1989; 13:461-7
76. Brun R Tribouilloy C, Duval AM, Iserin L, Meguira A,
Pelle G, Dubois-Rande JL: Left ventricular flow propaga-
tion during early filling is related to wall relaxation: a
color M-mode Doppler analysis. J Am Coll Cardiol
1992;20:420-32
77. Yamamoto K, Masuyama T, Tanouchi J, Naito J, Mano T,
Kondo H, Nagano R, Hori M, Kamada T: lntraventricular
dispersion of early diastolic filling: a new marker of left
ventricular diastolic dysfunction. Am Heart J 1995;
129:291-9
78. Appleton CR Carucci MJ, Henry CP, Olajos M: Influence
of incremental changes in heart rate on mitral flow veloc-
ity: assessment in lightly sedated, conscious dogs. J Am
Coll Cardiol 1991;17:227-36
79. Choong CY, Abascal VM, Thomas JD, Guerrero JL,
McGlew S, Weyman AE: Combined influence of ventric-
ular loading and relaxation on the transmitral flow veloc-
ity profile in dogs measured by Doppler echocardiogra-
phy. Circulation 1988;78:672-83
80. Herve C, Duval AM, Malak J, Meguira A, Brun P: Rela-
tions between posterior wall kinetics during diastole and
left ventricular filling. J Am Coll Cardiol 1990;15:
1587-93
Brutsaert and Sys 241
81. Stoddard MF, Pearson AC, Kern MJ, Ratcliff J, Mrosek
DG, Labovitz AJ: Left ventricular diastolic function:
comparison of pulsed Doppler echocardiographic and
hemodynamic indexes in subjects with and without coro-
nary artery disease. J Am Coll Cardiol 1989;13:327-36
82. Bareiss P, Facello A, Constantinesco A, Demangeat JL,
Brunot B, Arbogast R, Roul G: Alterations in left ventric-
ular diastolic function in chronic ischemic heart failure:
assessment by radionuclide angiography. Circulation
1990;81 :III-71-7
83. Scalia GM, Greenberg NL, McCarthy PM, Thomas JD,
Vandervoort PM: Nonivasive assessment of the ventricu-
lar relaxation time constant (x) in humans by Doppler
echocardiography. Circulation 1997 ;95:151-5
84. Fisch C, Beller GA, DeSanctis RW, Dodge HT, Kennedy
JW, Reeves TJ, Weinberg SL: Task force on assessment
of diagnostic and therapeutic cardiovascular procedures
(Subcommittee to Develop Guidelines for Clinical Appli-
cation of Echocardiography): ACC/AHA Task Force
Report. Circulation 1990;82:2323-45
85. Zoghbi WA, Bolli R: The increasing complexity of
assessing diastolic function from ventricular filling
dynamics. J Am Coll Cardiol 1991;17:237-8
86. Brecker SJD, Gibson DG: Echocardiographic evaluation
of ventricular diastolic function: implications for treat-
ment. Heart 1996;76:386-7
87. Klodas E, Nishimura RA, Appleton CR Redfield MM,
Oh JK: Doppler evaluation of patients with constrictive
pericarditis: use of tricuspid regurgitation velocity curves
to determine enhanced ventrieular interaction. J Am Coll
Cardiol 1996;28:652-7
88. Zile MR, Gaasch WH: Mechanical loads and the isovolu-
mic and filling indices of left ventricular relaxation. Prog
Cardiovasc Dis 1990;32:333-46
89. Blaustein AS, Gaasch WH: Myocardial relaxation: VI.
Effects of ~-adrenergic tone and asynchrony on LV relax-
ation rate. Am J Physiol 1983; 244:H417-22
90. Little WC: Enhanced load dependence of relaxation in
heart failure: clinical implications. Circulation 1992;85:
2326-8
91. Brutsaert DL, Claes VA, Sonnenblick EH: Effects of
abrupt load alterations on force-velocity-length and time
relations during isotonic contractions of heart muscle:
loadclamping. J Physiol (London) 1971;216:319-30
92. Aronow WS, Kronzon I: Effect of enalapril on congestive
heart failure treated with diuretics in elderly patients with
prior myocardial infarction and normal left ventricular
ejection fraction. Am J Cardiol 1993;71:602-4
93. Setaro JF, Zaret BL, Schulman DS, Black HR, Sourer R:
Usefulness of verapamil for congestive heart failure asso-
ciated with abnormal left ventricular diastolic filling and
normal left ventricular systolic performance. Am J Car-
diol 1990;66:981-6
94. Suwa M, Hirota Y, Kawamura K: Improvement in left
ventricular diastolic function during intravenous and oral
diltiazem therapy in patients with hypertrophic cardiomy-
opathy: an echocardiographic study. Am J Cardiol 1984;
54:1047-53
95. Dash H, Copenhaver GL, Ensminger BA: Improvement
in regional wall motion and left ventricular relaxation
242 Journal of Cardiac Failure Vol. 3 No. 3 September 1997
after administration of diltiazem in patients with coronary
artery disease. Circulation 1985;72:353-63
96. Szlachcic J, Tubau JF, Vollmer C, Massie BM: Effect of
diltiazem on left ventricular mass and diastolic filling in
mild to moderate hypertension. Am J Cardiol 1989;63:
198-201
97. Dahl6f B, Pennert K, Hansson L: Reversal of left ventric-
ular hypertrophy in hypertensive patients: a metaanalysis
of 109 treatment studies. Am J Hypertens 1992;5:95-110
98. Lewis BS, Merdler A: Improvement of diastolic function
by nisoldipine in patients after acute myocardial infarc-
tion. J Cardiovasc Pharmacol 1996;28(suppl. 2):$36-9
99. Sato H, Hori M, Ozaki H, Yokoyama H, Imai K,
Morikawa M, Takeda H, Inoue M, Karnada T: Exercise-
induced upward shift of diastolic left ventricular pres-
sure-volume relation in patients with dilated cardiomy-
opathy: effects of [3-adrenoceptor blockade. Circulation
1993;88:2215-23
100. Pfeffer MA, Lamas GA, Vaughan DE, Parisi AF, Braun-
wald E: Effect of captopril on progressive ventricular
dilatation after anterior myocardial infarction. N Engl J
Med 1988;319:80-6
101. Litwin SE, Katz SE, Morgan JP, Douglas PS: Long-term
captopril treatment improves diastolic filling more than
systolic performance in rats with large myocardial infarc-
tion. J Am Coil Cardiol 1996;28:773-81
102. Hayashida W, Donckier J, Van Mechelen H, Charlier AA,
Pouleur H: Diastolic properties in canine hypertensive
left ventricular hypertrophy: effects of angiotensin con-
vetting enzyme inhibition and angiotensin II type-1
receptor blockade. Cardiovasc Res 1997;33:54-62
103. Friedrich SP, Lorell BH, Rousseau MF, Hayashida W,
Hess OM, Douglas PS, Gordon S, Keighley CS, Benedict
C, Krayenbuehl HP, Grossman W, Pouleur H: Intracardiac
angiotensin-converting enzyme inhibition improves dias-
tolic function in patients with left ventricular hypertrophy
due to aortic stenosis. Circulation 1994;90:2761-71
104. Diez J, Laviades C, Mayor G, Gil MJ, Monreal I:
Increased serum concentrations of procollagen peptides
in essential hypertension: relation to cardiac alterations.
Circulation 1995 ;91:1450-6
105. Konstam MA, Kronenberg MW, Rousseau MF, Udelson
JE, Melin J, Stewart D, Dolan N, Edens TR, Ahn S,
Kinan D, Howe DM, Kilcoyne L, Metherall J, Benedict
C, Yusuf S, Pouleur H: Effects of the angiotensin convert-
ing enzyme inhibitor enalapril on the long-term pro-
gression of left ventricular dilatation in patients with
asymptomatic systolic dysfunction. Circulation 1993;88:
2277-83
106. Philbin EF, Rocco TA: The utility of angiotensin-convert-
ing enzyme inhibitors in heart failure with preserved left
ventricular systolic function. J Am Coil Cardiol 1997;
29(suppl. A):324A
107. Vantrimpont E Rouleau JL, Wun CC, Ciampi A, Klein
M, Sussex B, Arnold JMO, Moy6 L, Pfeffer M: Additive
beneficial effects of beta-blockers to angiotensin-convert-
ing enzyme inhibitors in the survival and ventricular
enlargement (SAVE) study. J Am Coll Cardiol 1997;29:
229-36
108. Brodie BR, Grossman W, Mann T, McLaurin LP:
Effects of sodium nitroprusside on left ventricular dias-
tolic pressure-volume relations. J Clin Invest 1977;59:
59-68
109. Bonow RO, Dilsizian V, Rosing DR, Maron BJ,
Bacharach SL, Green MV: Verapamil-induced improve-
ment in left ventricular diastolic filling and increased
exercise tolerance in patients with hypertrophic car-
diomyopathy: short- and long-term effects. Circulation
1985;72:853-64
110. Paulus WJ, Lorell BH, Craig WE, Wynne J, Murgo JP,
Grossman W: Comparison of the effects of nitroprusside
and nifedipine on diastolic properties in patients with
hypertrophic cardiomyopathy: altered left ventricular
loading or improved muscle inactivation? J Am Coll Car-
diol 1983;2:879-86
111. Pouleur H, Van Eyll C, Gurn6 O, Rousseau MF: Analysis
of the mechanisms underlying the changes in left ventric-
ular filling dynamics during oral nisoldipine therapy in
patients with anterior myocardial infarction. Eur Heart J
1992;13:952-9
112. Lahiri A, Rodrigues EA, Carboni GP, Raftery EB: Effects
of long-term treatment with calcium antagonists on left
ventricular diastolic function in stable angina and heart
failure. Circulation 1990;81:III-130-8
113. Stauffer JC, Gaasch WH: Recognition and treatment of
left ventricular diastolic dysfunction. Prog Cardiovasc
Dis 1990;32:319-32
114. Shah AM: Treatment of diastolic dysfunction: modula-
tion of endothelial function. Heartforum 1997;10(suppl.
1):84-9
115. Matsumori A, Shioi T, Yamada T, Matsui S, Sasayama S:
Vesnarinone, a new inotropic agent, inhibits cytokine pro-
duction by stimulated human blood from patients with
heart failure. Circulation 1994;89:955-8
116. Clarkson PBM, Wheeldon NM, Macleod C, Coutie W,
MacDonald TM: Brain natriuretic peptide: effect on left
ventricular filling patterns in healthy subjects. Clin Sci
1995;88:159-64
117. Clarkson PBM, Wheeldon NM, MacFadyen RJ, Pringle
SD, MacDonald TM: Effects of brain natriuretic peptide
on exercise hemodynamics and neurohormones in
isolated diastolic heart failure. Circulation 1996;93:
2037-42
118. Yamamoto K, Burnett JC Jr, Redfield MM: The endoge-
nous natriuretic peptide system modulates diastolic func-
tion in experimental heart failure. J Am Coll Cardiol
1997;29(suppl. A):501A
119. Paulus WJ, Vantrimpont PJ, Shah AM: Paracrine coro-
nary endothelial control of left ventricular function in
humans. Circulation 1995;92:2119-26