Download Heart failure with preserved ejection fraction. Diastolic dysfunction

Cardiovascular Research 64 (2004) 9 – 11
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Editorial
Heart failure with preserved ejection fraction. Diastolic dysfunction,
subtle systolic dysfunction, systolic-ventricular and arterial stiffening,
or misdiagnosis?
Paul Steendijk*
Department of Cardiology, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands
Received 15 July 2004; accepted 20 July 2004
See article by He et al. [19] (pages 72–83) in this issue.
Patients with signs and symptoms of congestive heart
failure (CHF) may present with a normal left ventricular (LV)
ejection fraction (EF). Epidemiological studies indicate that
about half of the CHF patients in the community have a
relatively normal or preserved EF (typically defined as
EFN50%) [1–3]. This finding appears to be in line with
hospital-based studies, but the heterogeneity in patient
selection, diagnostic criteria for CHF, and methods for
assessment of systolic function makes it difficult to compare
these studies [4]. Compared to patients with CHF and
depressed EF, patients with CHF and preserved EF are older,
are more often women, more frequently have a history of
hypertension, and less frequently have coronary artery
disease [1–4]. CHF is the most frequent cause of hospitalization in persons 65 years of age or older, and a recent largescale, population-based study [5] indicates a prevalence for
CHF of 4.9% in this age group. Interestingly, only 22% of
these CHF patients had overtly impaired LV systolic function
(defined as EFb45%). Of note is that the mean age of patients
represented in the major CHF treatment trials is typically 59–
65, whereas the mean age of patients in the community at the
time of first diagnosis of CHF appears to be about 77 [1,6].
It is often assumed that the prognosis of CHF patients is
better for those with a preserved EF. This notion is
supported by the meta-analysis by Vasan et al. [4] which
covers 31 studies on CHF with preserved EF performed
between 1970 and 1995. The reported annual mortality rate
in the reviewed studies ranged between 1.3% and 17.5%.
* Corresponding author. Tel.: +31 71 526 2020; fax: +31 71 526 6809.
E-mail address: [email protected].
This wide range is partly related to variation in the patient
selection criteria and to the different definitions for
preserved systolic function used in the various studies. In
addition, the findings are biased by the mean age of the
included subjects. If we discard the studies in which mean
age was N80 years, the highest reported annual mortality
was 9%. This is substantially better than the prognosis
which follows from studies in patients with CHF and low
EF [7]. Recently, Thomas et al. [8] published an overview of
61 studies performed between 1966 and 2001. The evidence
on outcome from the reviewed studies is partly contradictory, but tends to show lower hospitalization rates and
mortality rates in CHF with preserved EF compared to
depressed EF. However, it should be noted that several
studies report that the longer-term mortality is similar.
Furthermore, series in elderly cohorts with CHF show very
similar mortality rates among those with preserved and
depressed EF.
Despite the fact that CHF with preserved EF is very
common and causes significant morbidity and mortality,
optimal treatment or even guidelines for these patients have
not been defined. This is in sharp contrast to CHF with low
EF for which various large scale, double-blind, randomized,
placebo-controlled trials have identified treatment strategies
that reduce morbidity and mortality. However, several
randomized clinical trials are ongoing that examine treatment of CHF with preserved EF: PEP-CHF [9] investigates
ACE inhibitor perindopril, SENIORS [10] focuses on
nebivolol, a beta-1-selective blocker with vasodilating
properties, and MCC-135GO1 [11] tests a compound,
caldaret, that modulates calcium homeostasis. These trials
will all report in 2004. The first substantial trial in CHF
patients with preserved EF was published in the Lancet in
0008-6363/$ - see front matter D 2004 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.cardiores.2004.07.015
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P. Steendijk / Cardiovascular Research 64 (2004) 9–11
2003 and investigated the effects of an angiotensin receptor
blocker, candesartan [12]. This trial is part of the CHARM
program, which compared candesartan with placebo in
patients with depressed EF both with ACE inhibitors
(CHARM-Added) and without ACE inhibitors (CHARMAlternative), and in patients with preserved EF (CHARMPreserved). In CHARM-Added and CHARM-Alternative,
overall mortality, cardiovascular death, and hospitalization
for CHF were all significantly reduced; however, the results
from CHARM-Preserved were less conclusive and only
showed a reduction in hospitalization. Clearly, whereas data
on prevalence and prognosis of CHF with preserved EF are
available, data on effects of treatment are still very scant.
Therefore, at this point treatment of these patients remains
empirical and there is a great need for studies that provide
evidence-based management strategies.
In addition, the pathophysiological mechanisms underlying CHF with preserved EF need to be further clarified. It
has been proposed that virtually all of these patients exhibit
abnormal diastolic function. This view is substantiated in an
editorial by Zile [13]. In an earlier paper, Zile et al. [14]
measured pressure-derived and echo-Doppler-derived indices of diastolic function and found that one or more indexes
were abnormal in every patient with CHF and preserved EF.
It was concluded, therefore, that objective evidence of
abnormal LV relaxation, filling, or distensibility is not
necessary to make the diagnosis of diastolic heart failure in
this group of patients. However, some limitations and caveats
should be mentioned. First, primary right heart failure and
left-sided valvular disease may also lead to CHF with
preserved EF, and such patients should thus be excluded.
Obviously, alternative non-cardiac causes for symptoms,
such as obesity and lung disease, should also be rigorously
investigated to avoid misdiagnosis [15]. Furthermore, Burkhoff et al. [16] argue that the only way to truly demonstrate
clinically relevant abnormalities of diastolic properties is by
showing changes (i.e. upward shifts) of the ventricular enddiastolic pressure–volume relationship, since echocardiographic parameters of diastolic function are load-dependent
and cannot be viewed as specific indices of passive diastolic
function [17]. However, Zile’s group has taken up this
challenge and very recently provided additional evidence that
abnormal active relaxation and increased passive stiffness is
generally present in these patients [18]. Although there is
little doubt that diastolic dysfunction plays an important role
in many patients with CHF and preserved EF, there are other
mechanisms that deserve attention.
In this issue of Cardiovascular Research, He et al. [19]
present a study in dogs that received daily coronary
microembolization until an end-diastolic pressure N18 mm
Hg was reached. The animals subsequently developed overt
signs of heart failure. The authors found that a subgroup had
preserved EF and dP/dt max, and examined diastolic function
in these animals by detailed analysis of ventricular pressure–
volume relations. No consistent changes in diastolic
function were found, leading to the conclusion that CHF
with preserved EF does not automatically imply diastolic
dysfunction. The authors propose that a more subtle systolic
impairment, which was evident from parallel shifts of the
systolic pressure–volume relations but not detected by EF or
dP/dt max, was sufficient to cause neurohormonal activation,
intravascular volume expansion, and elevated end-diastolic
pressure to a degree comparable with that found in animals
with reduced EF and dP/dt max. Therefore, a message from
this paper would be that measurement of EF (or even dP/
dt max) is not sufficient to exclude systolic dysfunction as the
primary cause of CHF. A similar conclusion was reached
earlier by Petrie et al. [20] who proposed to use atrioventricular plane displacement as a more sensitive echocardiographic marker. Interestingly, in He’s study the position of
the end-systolic pressure–volume relation rather than its
slope (end-systolic elastance) proved to be the most
sensitive marker of systolic dysfunction. This confirms
previous findings from our group in an animal model with a
critical coronary stenosis [21] and suggests that absolute
end-systolic volume is a valuable index of subtle systolic
dysfunction. A potential limitation of HeTs study is that the
animal model may not reflect some typical characteristics of
CHF with preserved EF in humans. One particular finding
was that vascular afterload decreased following development of CHF in the animals with preserved EF, whereas it
was maintained in the animals with reduced EF. Thus, this
decrease in afterload may very well explain the preserved
EF. However, a recent study by Kawaguchi et al. [22] shows
that patients with CHF and preserved EF have an increased
arterial stiffening (beyond that expected with aging and/or
hypertension), and the authors speculate that the arterial
stiffening, combined with the ventricular systolic stiffening
that was also found in these patients, elevates systolic load
to prolong relaxation, compromizes filling, and raises enddiastolic pressure. The importance of arterial stiffening is
also shown in a study by Hundley et al. [23] showing that
this parameter closely correlates with exercise tolerance in
older persons with CHF and preserved EF. The paper
provides strong evidence that reduced aortic distensibility is
a possible cause of cardiac failure in these patients.
In conclusion, it is likely that the pathophysiology of
heart failure with preserved EF is heterogeneous. Cardiac
failure may be caused primarily by diastolic dysfunction, by
subtle systolic dysfunction, or result from excessive arterial
stiffening. Further research into the underlying mechanisms
is needed because each may require a different treatment. If
so, identification of reliable markers and finding appropriate
methods to determine these markers would be the next step
to optimize treatment of this very large group of patients.
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