European Journal of Heart Failure 9 (2007) 136 – 143

www.elsevier.com/locate/ejheart

Review
Systolic and diastolic heart failure: Different phenotypes of the
same disease?
Gilles W. De Keulenaer ⁎, Dirk L. Brutsaert
Department of Physiology, University of Antwerp, Antwerp, Belgium and Division of Cardiology, Middelheim Hospital, Groenenborgerlaan 171,
2020 Antwerpen, Belgium
Received 26 October 2005; received in revised form 20 February 2006; accepted 24 May 2006
Available online 1 August 2006

Abstract

Traditional pathophysiological concepts of chronic heart failure have largely focused on the haemodynamic consequences of ventricular
systolic dysfunction. How these concepts relate to the pathophysiology of diastolic heart failure, i.e., heart failure with a preserved ejection
fraction is, however, unclear, causing uncertainty about pathophysiology, diagnosis and management.
Recent measurements of regional myocardial systolic function in patients with diastolic heart failure indicate that systolic and diastolic
heart failure may be more closely related than previously anticipated. Rather than being considered as separate diseases with a distinct
pathophysiology, systolic and diastolic heart failure may be merely different clinical presentations within a phenotypic spectrum of one and
the same disease. In this review, we will interpret these new insights in a broader conceptual context of chronic heart failure and design novel
paradigms in which systolic and diastolic heart failure jointly progress in a pathophysiological time trajectory of only one disease.
© 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Keywords: Chronic heart failure; Diastole; Relaxation; Ventricular function

1. Introduction exacerbations triggered by atrial fibrillation, hypertension,

Epidemiological studies have established that the inci-
dence of chronic heart failure is increasing [1,2]. These
studies have also revealed that about half of the patients with
chronic heart failure have a normal left ventricular ejection
fraction (> 50%). Although originally viewed as a mild
disease, it now appears that heart failure at a preserved
ejection fraction (HFprEF) leads to an increased annual
mortality of 5–8% (compared with 10–15% for patients with
systolic heart failure). [3–5] In patients over 70 years old, the
mortality rates for HfprEF and heart failure at reduced
ejection fraction may be nearly equal. With respect to
morbidity, the impact of HFprEF is high with readmission
rates being similar to heart failure at reduced ejection fraction
(6-month all-cause readmission rate 45%) [6,7], reflecting
the episodic clinical course of the disease with sudden
⁎ Corresponding author. Tel.: +32 3 2653 277; fax: +32 3 2653 276.
E-mail address: gilles.dekeulenaer@ua.ac.be (G.W. De Keulenaer).
1388-9842/$ - see front matter © 2006 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejheart.2006.05.014
infections, medical non-compliance, etc. [8].
Despite these observations, consensus on the definition
and diagnostic criteria of this syndrome is still missing [9–
12]. The syndrome is randomly called “heart failure with
preserved ejection fraction” or “diastolic heart failure”, or–
erroneously as we will see later–“heart failure with
preserved systolic function”. Traditional concepts and
clinical trial design in chronic heart failure have largely
focused on the haemodynamic consequences of heart
failure with a reduced ejection fraction (“systolic heart
failure”), leaving HFprEF as a “separate” disease with no
consensus on the pathophysiology and without proven
therapy.
Yet, how strong is the evidence that the mechanical pump
abnormalities observed in HFprEF (ventricular relaxation
disturbances and increased ventricular stiffness [13]) devel-
op independently from the (mal)adaptive forces in systolic
heart failure? Alternatively, is there enough evidence to
counter the hypothesis that the pathophysiology of HFprEF
 G.W. De Keulenaer, D.L. Brutsaert / European Journal of Heart Failure 9 (2007) 136–143 137

is essentially identical, or at least strongly related, to the
pathophysiology of systolic heart failure?
2. Need to adjust diagnostic criteria to new
pathophysiological insights
Despite numerous attempts to develop diagnostic
criteria for HFprEF, diagnostic guidelines have remained
unsatisfactory [14,15]. Critiques have been formulated
towards the overemphasis on the presence of diastolic
abnormalities on the one hand, and on the shortcomings
of using ejection fraction as a parameter of systolic
function. First, although impaired relaxation and genuine
diastolic abnormalities undoubtedly contribute to symp-
toms and in fact are found in all patients with HFprEF
[16], a slow left ventricular relaxation pattern is observed
in many individuals without symptoms or signs of heart
failure. Hence, there is clearly a need to include supple-
mentary factors–i.e., “disease modifiers” as we will see
below–that may influence the clinical impact of impaired
relaxation.
Second, ejection fraction is a convenient measure of
overall haemodynamic pump dysfunction, but a poor
measure of systolic muscular pump dysfunction. Recent
studies on the mechanical ventricular properties in patients
diagnosed with HFprEF have consistently revealed abnor-
malities of left ventricular systolic function. For example,
performance of longitudinal myocardial fibers has been
measured by long-axis M mode echo or tissue Doppler
imaging (TDI) in patients with HFprEF. These measure-
ments revealed depressed contractile performance in patients
with HFprEF and in patients with asymptomatic diastolic
dysfunction, despite a preserved ejection fraction [17–26]
(Fig. 1).
These observations, therefore, support the hypothesis that
HFprEF and systolic heart failure may be more closely
related than previously anticipated. In other words, the
conjecture that HFprEF is a distinct disease in which systolic
myocardial function is preserved seems at least inaccurate.
HFprEF should, instead, be regarded as a variant form of
systolic heart failure, but in which symptoms and signs
develop prematurely. Although several investigators have
formulated this view previously [17–26], it nevertheless still
remains controversial, in part due to attempts by some to re-
define terms of cardiac performance. In our opinion, these
attempts have favoured existing uncertainties and misunder-
standings [27]. We will, therefore, briefly summarize these
misunderstandings, and explain how they should be re-
interpreted to become consistent with the insights reviewed
in this paper.
Misunderstanding 1: “Analysis of ventricular perfor-
mance in HFprEF does not show systolic abnormalities.”
It has been recently established [27,28] that parameters of
global systolic performance of the left ventricle on cardiac
catheterization (stroke work, preload recruitable stroke work,
ejection fraction, systolic stress-shortening relationship, end-
systolic pressure–volume relationship, and peak (+)dP/dt) in
patients with HFprEF were not different from control
patients and that only parameters of left ventricular
relaxation and diastolic stiffness were impaired. From
these observations, the investigators concluded that the
“pathophysiology of HFprEF does not appear to be related to
significant abnormalities in the systolic properties of the left
ventricle”.
Above-mentioned conclusions seem reasonable enough,
as long as one views the heart as a mere haemodynamic
pump as historically proposed by Wiggers [29], Rushmer
[30] and Sarnoff [31]. From the observations by Abbott and
Mommaerts [32] and Sonnenblick [33], it became clear,
however, that any evaluation of cardiac performance ought
to include, in addition, some properties of cardiac muscle. If
perceived as a mere haemodynamic [26,27], rather than as a

Fig. 1. Heart failure with preserved ejection fraction is commonly accompanied by various degrees of systolic dysfunction. (A) Systolic/mitral annular amplitude
by long-axis M mode echo (S lax) reveals a significant decrease in systolic function in diastolic heart failure (DHF), despite preserved ejection fraction
(LVEF > 45%) (reproduced from Yip et al. [18], with permission from the BMJ Publishing Group). (B) Mean regional myocardial sustained systolic velocity
(mean SM) from a 6-basal segmental model by tissue Doppler imaging (TDI) has been plotted as a function of ejection fraction in four groups of patients, i.e.,
controls, diastolic dysfunction (DD), diastolic heart failure (DHF), and systolic heart failure (SHF). Importantly, in the lower right quadrant of this scatter plot,
mean SM has significantly decreased in about 50% and 15% of patients with DHF and DD, respectively, despite preserved ejection fraction >50% (reproduced
from Yu et al. [17], with permission).
138 G.W. De Keulenaer, D.L. Brutsaert / European Journal of Heart Failure 9 (2007) 136–143
muscular pump, the above measurements are, therefore, at
least incomplete.
From the perception of a traditional haemodynamic
pump, preservation of peripheral perfusion pressure, stroke
volume, and cardiac output (blood flow)–as well as all
related or derived parameters, such as, e.g., stroke work,
pressure–volume and stress-shortening relations, +dP/dt and
other derivatives–is of key importance. In normal condi-
tions, the higher end-diastolic volume, the higher is stroke
volume, the ratio of stroke volume-to-end-diastolic volume
being calculated as the ejection fraction, which remains
constant. Under stress (e.g., after an acute myocardial
infarction), the heart is able to maintain stroke volume, as
well as peripheral flow and perfusion pressure; hence, hae-
modynamic pump performance, constant for some time, but
only at the expense of an inappropriately increased end-
diastolic volume with concomitant ventricular remodelling.
The ensuing progressive decline in calculated ejection
fraction must, therefore, be seen as an early sensitive sign
of this inappropriately increased end-diastolic volume and
remodelling, and hence, of haemodynamic pump failure.
Regional and temporal contractile properties of ventric-
ular cardiac muscle are, however, most often impaired at a
much earlier stage. Hence, consistent with recent echo-
Doppler analysis [17–25]–particularly in hearts with
concentric hypertrophy that are hampered somehow to
increase their end-diastolic volume–substantial systolic
dysfunction at rest and during adrenergic stimulation [34]
may be present already when mean overall haemodynamic
pump performance, including its most sensitive mechanical
index ejection fraction, is still well preserved. In addition to
myocardial temporal and regional non-uniformities, this
early stage of systolic dysfunction is also characterized by
significant left ventricular relaxation abnormalities, i.e., in
rate and time of onset. Importantly, in a muscular–unlike a
haemodynamic–pump, ventricular relaxation should be
regarded as an intrinsic part of systole. Moreover, as the
haemodynamic pump index ejection fraction is blind for
such early changes in cardiac muscular pump performance,
it is too insensitive, hence inappropriate, to characterize a
group of patients with symptoms of heart failure resulting
from such abnormalities, i.e., diastolic heart failure, as being
distinct from other patients with chronic heart failure. A
fortiori, therefore, measurements advocated by some [27,28]
of haemodynamic pump performance–some of which being
less sensitive still than ejection fraction–can hardly provide a
sufficiently solid argument to conclude that the “pathophys-
iology of HFprEF does not appear to be related to significant
abnormalities in the systolic properties of the left ventricle.”
Misunderstanding 2: “HFprEF does not fit within current
pathophysiological paradigms of chronic heart failure”.
In a traditional conceptual view on the pathophysiology
of chronic heart failure, cardiac function is regarded as
evolving within a vicious circle of (de)compensatory
mechanisms, gradually and irreversibly spiralling down
until end-stage pump failure, or until death ensues
prematurely. This pathophysiological model is most suitable
to illustrate the complementary contribution of the underly-
ing systemic (mal)adaptative reactions, i.e., haemodynamic
overload, neurohormonal activation, enhanced pro-inflam-
matory cytokine activity and endothelial dysfunction [35]. A
disadvantage of this model is, however, that it lacks a time
dimension, thereby neglecting the time-dependent evolution
of symptom severity. In clinical practice, the symptoms in
many patients, especially those with HFprEF, evolve clearly
out of phase with the pathophysiological progression of
overall pump dysfunction. As this important paradox of
chronic heart failure remains unappreciated, HFprEF does
not seem to fit within the above traditional paradigm of
chronic heart failure. In the following paragraphs, we will,
therefore, review two alternative paradigms of chronic heart
failure and investigate how their pathophysiology relates to
HFprEF.
3. Diastolic heart failure and alternative paradigms of
chronic heart failure
3.1. A time-dependent progression model of chronic heart
failure
In a time-dependent model of chronic heart failure,
depicted in Fig. 2 as a time trajectory of cardiac pump
performance, the progression of chronic heart failure can be
subdivided in three consecutive pathophysiological stages.
Under stress, the heart recruits various compensatory
autoregulatory mechanisms. A fundamental feature of this
first and very early “systolic activation” or pre-disease stage
is the capacity of the heart to delay the onset of ventricular
relaxation. This often ignored or underestimated feature
allows the ventricle to modulate systolic time duration
during which a given amount of stroke work is delivered
[36–38]. In a second stage (“mild systolic dysfunction”), as
commonly observed during the initial phases of myocardial
hypertrophy and ischemia, the above autoregulatory
mechanisms become maladaptive. Typically, ventricular
relaxation either regionally or globally becomes abnormally
slow and impaired with a progressive loss of the ventricle to
modulate the timing of onset of relaxation. It can be
commonly detected as an abnormal mitral inflow signal
during Doppler echocardiography (E/A inversion). Impaired
relaxation is caused by three major processes, including (i)
dysfunction of intracellular myocardial inactivation process-
es, (ii) inappropriate loading—including those induced by
arterial elastance abnormalities and (iii) excessive non-
uniformity [36–39]. Besides relaxation disturbances, the
systolic function abnormalities of the ventricular muscular
pump can be objectified by TDI, by abnormal systolic time
intervals and by increased BNP levels [24]. During this
second “mild systolic dysfunction” stage, haemodynamic
pump performance, as reflected by the ejection fraction
(> 50%) is well preserved thanks to a well-compensated
performance of the ventricular haemodynamic pump.
 G.W. De Keulenaer, D.L. Brutsaert / European Journal of Heart Failure 9 (2007) 136–143 139

Fig. 2. Time progression model of chronic heart failure. The pathophysiological as well as the clinical progression of chronic heart failure can only be understood
by studying overall pump performance as a trajectory in the ‘time’ domain. Upper: pathophysiological progression. Progressive deterioration of pump
performance typically evolves in successive stages. A first stage is a reversible, compensatory stage during which systolic function is activated. Subsequently,
some of the adaptive compensatory mechanisms may become maladaptive, i.p. during relaxation (mild systolic dysfunction), at stages where ejection fraction
(LVEF) has hardly declined. Below an ejection fraction of 45–50%, systolic function and pump performance are severely compromised and evolve towards full-
blown–mostly a combination of systolic and diastolic–pump failure. Lower: clinical progression. This diagram illustrates the paradox between the
pathophysiological progression as depicted by a single time trajectory, and its divergence from the concomitant clinical time progression as evident from the
superimposed clinical symptoms and signs in three patients with heart failure according to the NYHA Classification.

Finally during a third stage (“pump failure”), deterio-
rating haemodynamic pump performance may reach a
critical threshold as evident from an ejection fraction below
40–45% with severe systolic and diastolic abnormalities.
Meanwhile, hypertrophy of the ventricle irreversibly
evolves into so-called adverse remodelling. Adverse
remodelling is still an ill-defined term indicating the
presence of a number of structural and functional abnor-
malities, which may result in myocardial fibrosis/necrosis
and irreversible dilatation.
An advantage of this model is that the time progression of
the clinical symptoms of chronic heart failure can be
superimposed on the time trajectory of the above patho-
physiological progression. In chronic heart failure, it is
silently assumed as if the severity of clinical symptoms
develops uniformly in all patients and synchronously with
the severity of pump failure, in which NYHA class IV
symptoms occur at ejection fractions below 20% (e.g.,
patient A in Fig. 2 lower). The latter presentation does not,
however, comply with daily clinical practice and with the
observation that left ventricular ejection fraction correlates
poorly with exercise tolerance. Indeed, a large proportion of
heart failure patients in NYHA class III and IV may already
be diagnosed clinically at an earlier pathophysiological stage
of pump failure, e.g., with ejection fractions clearly above
30–40% (e.g., patient B in Fig. 2 lower) or even above 45–
50%, indicating that overall pump performance is preserved.
Importantly, as indicated above, in the latter patients systolic
abnormalities, including significant myocardial contraction–
relaxation non-uniformities and impaired relaxation can be
detected (e.g., patient C in Fig. 2 lower). The latter group
corresponds to patients with so-called HFprEF, and some-
times denoted–erroneously–as heart failure with preserved
systolic function.
Hence, superimposing symptom progression and patho-
physiological progression in a time-progression model of
140 G.W. De Keulenaer, D.L. Brutsaert / European Journal of Heart Failure 9 (2007) 136–143

chronic heart failure allows incorporation of HFprEF and
systolic heart failure within one and the same pathophysi-
ological time trajectory, in which the two types of heart
failure only differ in the onset of their clinical manifestation,
but not in the presence or absence of systolic abnormalities.
In terms of chronological stages of disease, HFprEF comes
earlier than systolic heart failure, suggesting that HFprEF
could perhaps progress into systolic heart failure. Consis-
tently, in a recent survey in predominantly hypertensive
African-American patients with LV hypertrophy and a
normal ejection fraction (EF), 18% developed a reduced
EF after a median follow-up of approximately 4 years, with a
markedly increased risk for this outcome when pulmonary
oedema was seen on a chest X-ray [40]. Similarly, in about
20% of patients hospitalised for acute heart failure and a
preserved ejection fraction, the ejection fraction was < 45%
during a follow-up visit 3 months later, this in absence of
intermediate acute coronary complications [41].
3.2. A phenotype model of chronic heart failure
In this model shown in Fig. 3, chronic heart failure is,
again, presented as one disease but with multiple patient-
specific diverging phenotypical trajectories. Each patient
follows his/her own distinct individual time trajectory of
progressively deteriorating pump performance, the trajectory
depending on a number of disease modifiers. In a large
group of heart failure patients, a wide spectrum of different
phenotypes can thus be identified, with two extreme
presentations at each end of the spectrum. On the far left,
patients suffer from primary diastolic dysfunction; at end
stage, these patients have non-dilated ventricles, normal or
high ejection fraction, high filling pressures and NYHA class
IV symptoms but no signs of even mild global or regional
systolic dysfunction, a disease that is probably non-existent.
On the far right, patients develop NYHA class IV symptoms
at a stage when diastolic function is normal and only
contractile dysfunction is apparent, a disease that is also
probably non-existent. An important recent study by Yotti et
al. [42] suggests that in patients with dilated cardiomyop-
athy, ventricular dilatation itself impairs diastolic filling by
enhancing convective deceleration; along with a slowed
relaxation, reduced elastic recoil, and displacement onto the
stiff portion of the passive pressure–volume relation,
increased convective deceleration may thus contribute to
diastolic dysfunction in the patients.
Accordingly, most if not all cases of heart failure (e.g.,
patients A, B and C of Fig. 3), are hybrids within this
spectrum with combined systolic and diastolic abnormalities
and with symptoms developing at normal, slightly reduced,
moderately reduced or severely reduced left ventricular
ejection fraction, the latter being an index of global
haemodynamic pump performance, rather than of systolic
function. The direction of the patient's trajectory towards a
heart failure phenotype with either preserved or reduced
ejection fraction depends, in our opinion, on a number of
disease modifiers in which genetic, molecular, environmen-
tal and phenotypical factors may interact.
Comparing clinical characteristics of heart failure
patients with either preserved or reduced ejection fraction

Fig. 3. Phenotype paradigm of chronic heart failure. As opposed to the fact that from a pathophysiological point of view, chronic heart failure progresses along a
single time trajectory, from a clinical point of view it progresses along an infinite number of time trajectories, unique for each patient individually. Hence, patients
may develop signs and symptoms of heart failure over a wide range of pathophysiological stages of the same disease, varying from stages with a preserved
ejection fraction (LVEF) to stages with a severely reduced ejection fraction and leading to a spectrum of heart failure phenotypes. Disease modifiers such as
gender, hypertension, ventricular hypertrophy, diabetes, age and body mass index determine, within a single pathophysiological trajectory, the time of onset of
signs and symptoms of heart failure. Consistently, in a cohort of heart failure patients, the incidence of these disease modifiers (here shown for female sex,
hypertension and diabetes) critically depends on the phenotype of the disease [42–44].
 G.W. De Keulenaer, D.L. Brutsaert / European Journal of Heart Failure 9 (2007) 136–143
can easily identify a number of important modifier candi-
dates. In Fig. 3 (lower), for example, gender, incidence of
hypertension and of diabetes have been compared for three
different groups of heart failure patients, i.e., with normal
(> 50%), slightly reduced (> 40%) or markedly impaired
(< 40%) ejection fractions, respectively [43–45]. Strikingly,
female gender, diabetes and hypertension were much more
common in the first group compared with the last group, and
at intermediate incidence in the second group. Based on these
observations, it is attractive to speculate that in each
individual patient, a set of disease modifiers (which probably
also include age, myocardial hypertrophy, physical fitness,
cholesterol levels, etc.) will influence the phenotypical
trajectory of heart failure. In other words, after a cardiac
insult, disease modifiers may direct the disease towards a
predominantly “systolic” or “diastolic” heart failure pheno-
type. If the modifier directs towards diastolic heart failure, it
will somehow prevent ventricular remodelling and dilatation
of systolic heart failure, and perhaps to some extent
prognosis. This phenomenon has been demonstrated for
diabetes, obesity, hypertension and hypercholesterolemia
[46–50].
Explaining underlying mechanisms through which dis-
ease modifiers affect the clinical course of heart failure is a
difficult challenge and a subject of ongoing research. Each of
the modifiers may influence or be influenced by systemic
physiological pathways (e.g., neurohormonal activity, endo-
thelial function, etc.), cardiac molecular properties (levels of
gene expression, post-translational modifications) and
genotypic characteristics (gene deletions, gene polymorph-
isms, etc). Females with myocardial injury/overload, for
example, express a sex-specific cluster of myocardial genes
during disease progression [51], whereas gene deletions
differently affect progression of heart failure in females and
males [52–54].
An interesting aspect in this discussion may be the link
between disease modifiers and cardiac molecular mechan-
isms that determine ventricular relaxation and stiffness as the
latter processes determine diastolic function, left ventricular
end-diastolic pressures and symptoms of heart failure [55–
57]. As previously shown [58–60], diastolic function is a
target for modification by most if not all of the mentioned
disease modifiers, including gender, diabetes, obesity,
sedentary life style, myocardial hypertrophy and hyperten-
sion. In a study by Fischer et al. [58] in the absence of these
modifiers, diastolic abnormalities were rare (4.3% vs 11.1%)
in the general population, even in the elderly. Importantly,
and consistent with the present hypothesis, diastolic
dysfunction recovered upon corrections of these modifiers,
at least for obesity [59] and sedentary lifestyle [60].
Furthermore, further down on a sub-cellular scale, a direct
molecular link (e.g., titin isoform expression, SERCA-2a
gene expression, abnormalities in high energy phosphate
metabolism and secondary impaired calcium sequestration
and matrix metalloproteinase activity) between the modifier
and diastolic dysfunction has been demonstrated for some
141
conditions, including age [61,62], hypertension [63,64] and
diabetes [65].
4. Conclusion: systolic and diastolic heart failure;
different phenotypes of the same disease
In the present review, we have discussed arguments
endorsing the hypothesis that HFprEF is a variant form of
systolic heart failure in which symptoms develop prema-
turely. Central to this discussion were considerations about
the heart as a muscular pump in which–unlike a mere
haemodynamic pump–the mechanical performance of the
heart was interpreted in terms of cardiac muscle as well as
cardiac pump parameters. Next, re-introducing time dimen-
sions in the disease progression model allowed the
incorporation of the pathophysiological as well as the
clinical manifestation of HFprEF within an overall patho-
physiological time trajectory of chronic heart failure. We
hypothesize, therefore, that from a pathophysiological point
of view systolic and HFprEF progress along a single
pathophysiological time trajectory. From a clinical point of
view, however, heart failure may progress along an infinite
number of time trajectories dependent on a complex
interaction of disease modifiers unique for each individual
patient. Accordingly, patients may develop signs and
symptoms of heart failure over a wide range of pathophys-
iological stages of the same disease, varying from stages
with mild systolic impairment (and a preserved ejection
fraction) to stages with severely depressed systolic function
(and severely reduced ejection fraction), leading to a
continuous spectrum of heart failure phenotypes. By
examining heart failure from this phenotype-oriented view,
disease modifiers and their underlying mechanisms should
be explored more carefully in clinical trials as they may
reveal crucial aspects and individualized therapeutic targets
of chronic heart failure. Clinicians should be conscious of
these ongoing developments prior to undertaking initiatives
for clinical trials and diagnostic as well as therapeutic
guidelines. In the mean time, therapy to improve prognosis
of HFprEF remains empirical and is essentially the same as
for systolic heart failure, as both diseases seem to be part of
the same disease process.
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