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Heart Failure
Heart Failure with Preserved Ejection Fraction
a report by
G i l l e s W D e K e u l e n a e r and D i r k L B r u t s a e r t
Department of Pharmacology, University of Antwerp
Definitions and Historical Considerations –
patients, measurements of LV ejection fraction do not allow for
The Misleading Role of Ejection Fraction
exclusion of any of these factors. Accordingly, rather than being two
Chronic heart failure (CHF) is a heterogeneous syndrome with a
separate identities, systolic and diastolic heart failure may be more
complex pathophysiology. Although many different definitions for
closely related than previously thought. In fact, it is preferable to
heart failure exist, we prefer the following: “a clinical syndrome
envisage CHF as a syndrome with a spectrum of diverse clinical
characterised by symptoms and signs of increased tissue/organ water
presentations, in which most if not all cases are hybrids of diastolic
and decreased tissue/organ perfusion. Regardless of its aetiology,
and systolic heart failure (see Figure 1). The misleading connotations
symptoms and signs may be related either to impaired left ventricular
of systolic and diastolic heart failure should be abandoned to avoid
(LV) relaxation, suction and filling (predominantly diastolic pump
biased clinical and scientific approaches.
dysfunction/failure) or to impaired output of the cardiac compression
pump (predominantly systolic pump dysfunction/failure) but almost
Systolic Abnormalities in Heart Failure with Preserved
always to a combination of both.”1
Ejection Fraction – The Heart as a Muscular Pump
The recent unveiling of LV systolic dysfunction at normal LV ejection
This definition of heart failure refrains from including any notion of LV
fraction by tissue Doppler imaging, magnetic resonance imaging (MRI)
ejection fraction. However, mostly driven by clinical trial design, heart
and speckle tracking is surprising at first glance. Nevertheless, these
failure has been dichotomised according to ejection fraction as
observations are just a reminder that LV ejection fraction is an index of
‘preserved’ (heart failure with preserved ejection fraction [HFpEF]) or
global haemodynamic pump performance, insensitive to disturbances
‘reduced’ (heart failure with reduced ejection fraction [HFredEF]).
of ventricular muscle function1 (see Figure 2). A preserved ejection
Recently, epidemiological surveys have revealed that the incidence of
fraction often merely indicates that the radial (or circumferential) fibres of
HFpEF has been steadily increasing over the past 25 years.2 Currently,
the ventricle have compensated for dysfunction of the longitudinal fibres;
the LV ejection fraction is found to be preserved in >50% of cases of
it does not necessarily imply that the systolic function of the muscular
heart failure. Patients with HFpEF appear to be older and are more
pump is normal. These considerations may have important diagnostic
likely to be female, have a history of hypertension and have less
implications, since impaired longitudinal fibre function may be the single
coronary artery disease. Once hospitalisation for ‘decompensation’ has
or most marked sign of cardiac dysfunction in HFpEF. Systolic impairment
occurred, the cardiovascular mortality and overall prognosis is as poor
of longitudinal fibre shortening strongly correlates with impairment of
as for HFredEF.
longitudinal fibre re-lengthening and with expression of brain natriuretic
2,3
peptide (BNP) messenger RNA (mRNA) in subendocardial LV layers.11
Erroneously, the pathophysiology of HFpEF and HFredEF were
considered to be genuinely different. Whereas HFredEF was correlated
with mere ‘systolic abnormalities’, these abnormalities were believed
to be absent in HFpEF. Instead, when ejection fraction was preserved,
heart failure was correlated with ‘diastolic abnormalities’, and was
thought to occur without abnormalities in systole. Inevitably, the
connotations ‘systolic’ and ‘diastolic’ heart failure were introduced as
they were estimated to reflect distinct diseases. However, recent
observations have neglected to refine this view.4,5 Most importantly, it
Gilles W De Keulenaer is a cardiologist at Middelheim
Hospital, where he serves as Director of the Centre for Heart
Failure and Cardiac Rehabilitation. He also serves as a
Professor of Physiology in the Department of Pharmacology
at the University of Antwerp. His core research interests
include physiological and molecular aspects of myocardial
and ventricular function, with a specific focus on
endothelial–cardiomyocyte cell communication.
E: [email protected]
is now generally recognised that in systolic heart failure LV diastolic
abnormalities are profound, and predict a patient’s symptoms better
than systolic (dys)function.6 In contrast, in diastolic heart failure there
are marked, previously overlooked LV systolic abnormalities, as
revealed by novel cardiac imaging techniques. 7 In fact, CHF,
irrespective of ejection fraction (even when preserved), is emerging as
a syndrome in which many pathophysiological processes interact.
These processes include systolic dysfunction,7 diastolic dysfunction,6
circulatory volume overload,8 disturbed ventriculo-arterial coupling9
and activation of neurohormonal systems.10 Although the relative
Dirk L Brutsaert is a Professor-Emeritus in the Department of
Pharmacology at the University of Antwerp. Between 1966
and 2002 he served as a Professor of Physiology and
Medicine in the Department of Medicine at the University of
Antwerp; from 1981 to 2002 he was Co-Chairman of the
Department of Cardiology at University Hospital Antwerp;
and he was an Honorary Consultant in the Department of
Cardiology at AZ Middelheim Hospital, University of
Antwerp, until 2006. Professor Brutsaert is Past President of
the Heart Failure Association of the European Society of
Cardiology (ESC) and of the Royal Academy of Medicine of
Belgium (both 2004–2006).
contribution of each of these factors may vary among individual
© TOUCH BRIEFINGS 2008
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Heart Failure
phenomenon, and it is influenced by many patient characteristics
Figure 1: Phenotypic Diversity of Chronic Heart Failure
acting as ‘disease modifiers’. LV remodelling, when quantified as
cardiomyocyte diameter, covers a wide, continuous spectrum over the
Cardiac
insult
whole range of LV ejection fraction.12 The ‘modifiers’ that influence LV
LVEF preserved
LVEF reduced
Slight
NYHA
remodelling include haemodynamic load, coronary arterial function,
Moderate
Severe
NYHA
Disease modifiers
I
Indi
II
vidu
a
l pa
III
tien
t tra
ject
IV
ory
gender, age, metabolic disturbances (obesity, diabetes), physical
I
fitness, cardiac endothelial function and genetic background, which
II
may either promote or decelerate remodelling. Future unravelling of
III
the cellular, molecular and biochemical puzzle of LV remodelling may
IV
reveal how these modifiers propel heart failure diversity over a wide
spectrum of closely related disease phenotypes.4
‘Diastolic’
heart failure
‘Systolic’
heart failure
Spectrum of phenotypes
Mechanisms of Left Ventricular Diastolic Dysfunction
Community
LVEF >50%
CHARM – ‘preserved’
LVEF >40%
MERIT-HF
LVEF >40%
73
40
23
Female (%)
Diastolic LV dysfunction is very common in, but not specific for, HFpEF. It
often co-exists with – or is even caused by – other cardiovascular
Hypertension (%)
78
64
44
abnormalities such as systolic LV dysfunction, arterial stiffening and
Diabetes (%)
46
28
25
volume overload. More specifically, diastolic LV dysfunction is a
Chronic heart failure (CHF) is a syndrome progressing along different time trajectories, and is unique to each
patient. During progression, disease severity and symptoms increase with variable changes on left ventricular (LV)
remodelling and, hence, on LV ejection fraction. The heart failure disease trajectory is influenced by numerous
patient characteristics that function as ‘disease modifiers’. These modifiers include diabetes, arterial hypertension
and female gender, which promote disease progression without eccentric LV remodelling and, hence, a preserved
ejection fraction. This phenomenon leads to increasing incidences of these modifiers in clinical trials and heart
failure surveys when LV ejection fraction in the inclusion criteria becomes higher (lower part of figure).
consequence of impaired LV suction due to impaired LV systolic
relaxation and reduced LV diastolic compliance.13 Causes of
impaired relaxation are related to factors intrinsic and extrinsic to
cardiomyocytes. The intrinsic factors include impaired inactivation
processes (disturbed intracellular calcium homeostasis, myofilament
function and cell energetics), whereas the extrinsic factors include
Figure 2: Subdivision of the Cardiac Cycle Taking Ventricular
Haemodynamic Pump and Ventricular Muscular Pump Approaches
pressure volume overload, ventricular dyssynchrony and abnormal activity
of soluble cardio-active factors (angiotensin, endothelin, nitric oxide).
Decreased compliance of the LV is due to extracellular matrix or
Haemodynamic
compression pump
Muscular pump
Diastole
Aorta
Systole
cytoskeletal abnormalities. Interestingly, none of the above mechanisms
of diastolic dysfunction seems to be specific for HFpEF or HFredEF,
V
P
F
Superficial
longitudinal
fibres
Inner
longitudinal
fibres
Inner
horizontally
looping fibres
Papillary
muscle
Vortex cordis
although there is emerging evidence that passive forces and resting
tension of cardiomyocytes from patients with HFpEF are higher than
those from patients with non-ischaemic HFredEF.12
Clinical Aspects of Heart Failure with
Preserved Ejection Fraction
Wiggers (1883–1963)
P
Brutsaert et al. (1964–)
Pump
f
Muscle
Diagnosis
1
The clinical symptoms and signs of patients with HFpEF are the same
Pump
P
V
Systole
t
4
1 2 3
Diastole
HFpEF =
diastolic failure
P
V
as for those with HFredEF. During diagnosis, the finding of a normal
t
4
3
Systole
Diastole
HFpEF =
systolo-diastolic failure
P
1
ejection fraction obviously should not be used to doubt the clinical
diagnosis of heart failure. Recently, the Heart Failure Association (HFA)
of the European Society of Cardiology (ESC) has proposed novel
diagnostic guidelines for heart failure when LV ejection fraction
is preserved14 (see Figure 3). Within these guidelines, blood flow
Doppler, tissue Doppler, serum BNP or N-terminal proBNP
(NT-pro-BNP) concentrations and atrial diameters play a central role.
2
3
4
V
3
4
V
The predictive values of BNP and NT-pro-BNP are still too vague to use
as the gold standard for diagnosis in individuals, but certainly reflect
Left: Wiggers’ traditional subdivision of the cardiac cycle with systole ending slightly before aortic valve closure.
Right: novel insight since the early 1960s into the intracellular physiological and pathophysiological mechanisms of
the heart as a muscular pump, which were obviously unknown in the Wiggers era, have logically led to
reconsidering the traditional Wiggers subdivision of the cardiac cycle. The figure compares the time traces (t) of an
the severity of disease when used in cohorts of HFpEF patients. In the
absence of atrial fibrillation, left atrial size provides morphological and
physiological evidence of chronic elevation in LV filling pressures.
afterloaded twitch in cardiac muscle (f = force; l = length) with the synchronised time traces of pressure (P) and
volume (V) of a ventricular haemodynamic pump. The similarity between the corresponding time traces has led to
the inclusion of isovolumic relaxation into systole of a ventricular muscular pump. Accordingly, the definition of
heart failure with preserved ejection fraction (HFpEF) as a systolo-diastolic disease, instead of a disease of isolated
diastolic function, depends on the acceptance of the function of the heart as a ventricular muscular pump.
Treatment of Heart Failure with
Preserved Ejection Fraction
Randomised multicentre trials in patients with HFpEF are scarce. Therefore,
The diversity of CHF does not reside in the presence or absence of
the recommendations for the management of HFpEF are based on small
systolic or diastolic dysfunction, but rather in the degree and type of
clinical studies lacking a pathophysiological concept and validated diagnostic
LV remodelling, developed along the pathophysiological progression
guidelines. Treatment of HFpEF should have two essential goals: reducing
of the disease. However, LV remodelling is not an all or nothing
symptoms and improving prognosis by targeting the mechanisms of disease.
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Heart Failure with Preserved Ejection Fraction
Symptom-targeted Treatment
Reducing the symptoms of individual patients with HFpEF can be
Figure 3: Diagnostic Flow Chart for Heart Failure with
Preserved Ejection Fraction
challenging as they may be multifactorial. For example, exertional
How to diagnose HFpEF?
dyspnoea, the most common symptom of HFpEF, can be caused by
increased LV diastolic pressures or reduced cardiac (chronotropic) reserve,
Symptoms or signs of heart failure
1
but also by peripheral deconditioning. Optimising therapy in HFpEF is
often a matter of trial and error, and can be frustrating when arterial
blood pressure is normal. Diastolic LV pressure can be reduced by
2
Preserved haemodynamic pump performance:
LVEF >50%, LVEDVI >97ml/m2
decreasing circulatory or LV volume (with diuretics, venodilators or
neurohormonal inhibitors), reducing heart rate to normal, reducing blood
pressure and maintaining synchronous atrial contraction. As treatment
3
Dysfunction of muscular pump performance resulting in
impaired relaxation, suction and filling
with diuretics can vary substantially, it may be appropriate to start at a
relatively low dosage, since a small change in diastolic volume may cause
a large change in pressure and cardiac output, and may lead to
hypotension. Blood pressure lability is often noted in HFpEF, not only due
to passive ventricular stiffening, but also due to arterial stiffening.
Invasive haemodynamic measurements:
mPCW >12mmHG or
LVEDP >16mmHg or
t >48ms or b >0.27
TD:
E/E’ >15
15>E/E’>8
Biomarkers:
NT-proBNP >220pg/ml
or BNP >200pg/ml
TD
E/E’ >8
Reducing heart rate in HFpEF acts as a double-edged sword. On the one
hand, it may have a beneficial impact on ischaemia-related diastolic
dysfunction, and may avoid the problem of incomplete relaxation seen at
high heart rates. On the other hand, blunting exercise-induced increases
Biomarkers:
NT-proBNP >220pg/ml
or BNP >200pg/ml
in heart rate may also inappropriately impair an important mechanism of
Echo – bloodflow Doppler
E/A >50yr <0.5 and DT >50yr >280ms
or Ard-Ad >30ms
or LAVI >40ml/m2 or
LVMI >122 g/m2 ( ): > 149g/m2 ( )
or atrial fibrillation
the (hypertrophic) heart to increase cardiac output, especially as some of
these hearts manifest a small recruitable inotropic and preload reserve,
and thus rely on chronotropy for adaptations of cardiac output to
HFpEF
peripheral demands.15
Consistent with the conceptual physiological considerations explained in Figure 2 and throughout the article,
Mechanism-targeted Treatment
the diagnostic criteria of heart failure with preserved ejection fraction (HFpEF) include the clinical demonstration
Randomised clinical trials on mechanism-targeted treatment in HpEF have
of a normal haemodynamic pump performance and a dysfunctional muscular pump performance. The latter can
be realised by invasive haemodynamic measurements, cardiac imaging techniques or using serum biomarkers.
been slow to develop. Thus far, none of the trials specifically
targeting HFpEF has shown a significant effect of either digoxin,
Perindopril for Elderly Persons with CHF (PEP-CHF) trial, a study in elderly
angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor
people with rather milder degrees of HFpEF (mean LV ejection fraction
inhibitors on overall mortality. In the Digitalis Investigation Group (DIG), in
65%), perindopril did not reduce overall mortality, perhaps because of low
those with ejection fraction >45% and ancillary sinus rhythm digoxin
event rates (4% per year), but significantly reduced hospitalisations for heart
induced a significant reduction in heart failure hospitalisations, but also a
failure.17 Of note, in some recent heart failure trials, inclusion criteria no
trend towards more hospitalisations for non-heart failures. In the
longer include limitations for ejection fraction, thereby studying heart failure
Candesartan in Heart Failure Assessment of Reduction in Mortality and
over the whole spectrum of ejection fraction. In one of such trials, the of the
Morbidity (CHARM)-preserved trial (heart failure with LV ejection fraction
Effects of Nebivolol Intervention on Outcomes and Rehospitalisation in
higher than 40%, but patient characteristics strongly diverging from HFpEF
Seniors With Heart Failure (SENIORS) trial, nebivolol reduced the composite
patients in the community), candesartan had a moderate but significant
end-point of death or cardiovascular hospitalisation, but the modest trend
impact on preventing hospital admissions for heart failure.16 Similarly, in the
towards improved mortality did not reach statistical significance.18 ■
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