Archives of Cardiovascular Disease (2008) 101, 361—372

Disponible en ligne sur www.sciencedirect.com

REVIEW

Treatment of heart failure with preserved systolic

function
Traitement de l’insuffisance cardiaque à fonction systolique préservée

P. de Groote a,∗, D. Herpin b, F. Diévart c, O. Hanon d,

J.N. Trochu e, J.Y. Artigou f, M. Galinier g, G. Habib h,
Y. Juillière i, Y. Neuder j, R. Roudaut k, M. Komajda l

a
Pôle cardiologie et médicine vasculaire, hôpital cardiologique, CHRU de Lille, boulevard du
Professeur-J.-Leclercq, 59037 Lille cedex, France
b
Service cardiologie, faculté de medicine et de pharmacie, CHU Poitiers, université Poitiers,
86021 Poitiers, France
c
Clinique Villette, 18, rue Parmentier, 59240 Dunkerque, France
d
Département de gériatrie, hôpital Broca, AP—HP, université Paris-Descartes—Paris-5,
54, rue Pascal, 75013 Paris, France
e
Clinique cardiologique et des maladies vasculaires, institut du thorax, CHU de Nantes,
boulevard Jacques-Monod, 44093 Nantes, France
f
Service de cardiologie, hôpital Avicenne, 125, route Stalingrad, 93009 Bobigny cedex, France
g
Pôle cardiovasculaire et métabolique, CHU Rangueil, TSA 50032, 31409 Toulouse cedex 9,
France
h
Service de cardiologie, hôpital la Timone, boulevard Jean-Moulin, 13005 Marseille, France
i
Département de cardiologie, CHU Nancy-Brabois, rue de Morvan, 54500
Vandoeuvre-les-Nancy, France
j
Service de cardiologie, CHU de Grenoble, B.P. 217, 38043 Grenoble cedex 9, France
k
Hôpital cardiologique Haut-Leveque, avenue Magellan, 33604 Pessac, France
l
Département de cardiologie, hôpital Pitié Salpetrière, AP—HP, université
Pierre-et-Marie-Curie—Paris-6, 47-83, boulevard de l’Hôpital, 75013 Paris, France

Received 10 December 2007; accepted 25 April 2008

Available online 7 July 2008

KEYWORDS Summary Heart failure is a major public health problem. Heart failure with preserved systolic
Heart failure; function (HF-PSF) is a common form, which is difficult to diagnose. Results of recent studies show
Diastolic heart that HF-PSF has a poor prognosis, with an annual survival rate similar to that of heart failure
failure; with left ventricular systolic dysfunction. Despite these findings, the therapeutic management
Diastolic dysfunction; of HF-PSF is not clearly defined. We will discuss in this review of the literature the current

∗ Corresponding author. Fax: +33 3 20 44 48 81.

E-mail address: pdgroote@chru-lille.fr (P. de Groote).

1875-2136/$ — see front matter © 2008 Published by Elsevier Masson SAS.

doi:10.1016/j.acvd.2008.04.008
362 P. de Groote et al.

therapeutic management of HF-PSF, including the role of precipitating factors such as hyper-
Preserved ejection tension, myocardial ischaemia and supraventricular arrhythmias, and the main results of
fraction; epidemiological registries and randomized controlled clinical trials in this disease. Only four
Treatment large therapeutic trials have assessed the impact of different classes of drugs (digoxin,
angiotensin II converting enzyme inhibitors, angiotensin II receptors type I blockers and beta-
blockers) on morbidity and mortality in HF-PSF. Results of these trials are disappointing. Apart
from the beta-blockers, the other three classes of drugs did not show benefit on the outcome
of the disease. Moreover, the results of the beta-blocker trial are controversial as a mixed
population of heart failure with and without preserved systolic function was studied. Finally,
the current therapeutic management of patients with HF-PSF is still based on our pathophys-
iological knowledge: education, low salt diet, diuretics, slowing heart rate and controlling
triggering factors. Other large randomized controlled multicenter trials, which may help us in
the understanding of HF-PSP and its therapeutic management, are ongoing.
© 2008 Published by Elsevier Masson SAS.

MOTS CLÉS Résumé L’insuffisance cardiaque est un problème majeur de santé publique. L’insuffisance
Insuffisance cardiaque à fonction systolique préservée (IC-FSP) est une forme fréquente dont le diagnostic
cardiaque ; est difficile. Les résultats des études récentes montrent que le pronostic de l’IC-FSP est mauvais
Insuffisance avec une survie annuelle proche de celle de l’insuffisance cardiaque par dysfonction systolique
cardiaque du ventricule gauche. Malgré ces données, la prise en charge thérapeutique de l’IC-FSP n’est
diastolique ; pas bien codifiée. Dans cet article, nous proposons une revue de la littérature sur cette prise en
Dysfonction charge thérapeutique. Nous nous sommes d’abord intéressés aux facteurs précipitant jouant un
diastolique ; rôle fréquent dans les épisodes de décompensation cardiaque : hypertension artérielle, ischémie
Fraction éjectée coronaire et troubles du rythme supraventriculaire. Puis, nous avons résumé la prise en charge
préservée ; thérapeutique des patients atteints d’IC-FSP inclus dans les registres épidémiologiques. Enfin,
Traitement les données issues des études thérapeutiques randomisées et contrôlées, peu nombreuses dans
cette pathologie, sont analysées. Seules quatre études d’envergure ont évalué l’impact cli-
nique de certaines classes médicamenteuses : la digoxine, les antagonistes des récepteurs de
l’angiotensine II, les inhibiteurs de l’enzyme de conversion de l’angiotensine II et les bêtablo-
quants. Les résultats de ces études sont décevants. Hormis, les bêtabloquants, les trois autres
classes médicamenteuses n’ont pas démontré d’effets bénéfiques sur l’évolution de la patholo-
gie. Pour les bêtabloquants, les résultats sont controversés, car la seule grande étude a inclus
une population mixte d’insuffisant cardiaque avec et sans fonction systolique préservée. Finale-
ment, en 2008, la prise en charge thérapeutique des patients ayant une IC-FSP reste basée sur
nos connaissances physiopathologiques : éducation, régime pauvre en sel, diurétiques, ralen-
tissement de la fréquence cardiaque et contrôle des facteurs déclenchant. D’autres études
multicentriques randomisées et contrôlées sont en cours qui nous permettront peut-être de
mieux comprendre l’IC-FSP et de mieux la prendre en charge.
© 2008 Published by Elsevier Masson SAS.

Heart failure with preserved systolic function (HF-PSF) is a
common, complex and severe disease. Its diagnosis is not
straightforward as it often affects elderly patients suffering
from multiple diseases. In order to better understand HF-
PSF, a French working group (the TACTIC group), proposed
a diagnostic algorithm based on the patient’s clinical data
and on the results of further investigations (Fig. 1) [1]. A
working group of the European Society of Cardiology pub-
lished a similar process leading to the same conclusions [2].
In the present article, the TACTIC group has tried to review
from the literature the current therapeutic management of
HF-PSF. For this purpose, our conclusions were based on arti-
cles published from 1985 to date and selected from medical
databases using the following keywords: heart failure, dias-
tolic heart failure, diastolic dysfunction, preserved ejection
fraction, treatment.
In the absence of significant results from random-
ized trials, the current treatment of HF-PSF is still
based on our pathophysiological knowledge. The major
factor in this disease is the increase in left ventricu-
lar end-diastolic pressure. Aim of the treatment is to
reduce the end-diastolic pressure and to avoid its sud-
den rise in certain circumstances. Kitzman et al. showed
that ventricular filling pressures increase significantly with
exercise in patients with isolated diastolic dysfunction
[3].
Together with the specific treatment of HF-PSF, pre-
cipitating factors or concomitant (or causative) diseases
involved in HF-PSF must be corrected. These are hyper-
tension, myocardial ischaemia and supraventricular arrhyth-
mias. Isolated left ventricular hypertrophy (LVH) or LVH
complicating hypertension predispose to the clinical expres-
sion of HF-PSF. Finally, HF-PSF generally occurs in the elderly
patient, who often has several comorbidities such as renal
failure, which contribute to the symptoms and the deterio-
ration of the disease.
Treatment of heart failure with preserved systolic function
Figure 1. Diagnostic algorithm for heart failure with preserved
systolic function proposed by the TACTIC group (from reference [1]).
Management of precipitating or causative
factors
Role of hypertension and left ventricular
hypertrophy
Pathophysiological review
Factors predisposing to LVH in the hypertensive
patient
The prevalence of electrical LVH depends on several param-
eters:
• blood pressure level, particularly systolic [4,5];
• duration of hypertension and its control by antihyperten-
sive treatment [6];
• age and obesity.
A sodium rich diet [7] and alcohol consumption [8]
also predispose to the development of LVH in hypertensive
patients. LVH occurs more commonly in hypertensive men;
however, the direct influence of sex disappears when the
severity of hypertension and lifestyle are taken into account
[9,10]. Finally, genetic and ethnic factors are also involved
[11,12].
363
Pathophysiological mechanisms of LVH in the hyper-
tensive patient
Several factors contribute to myocyte hypertrophy and
fibroblast proliferation.
Mechanical factors. Concentric LVH generally reflects
a process of myocyte adaptation to elevated blood pressure
(Laplace’s law), which becomes inappropriate and con-
tributes to the deterioration in left ventricular function.
In experimental models, genetically modified mice unable
to develop LVH when ventricular wall stress is increased by
applying an aortic ring, exhibit less degree of heart failure
than control animals, which develop hypertrophy [13]. The
role of arterial compliance and of central blood pressure in
the genesis of hypertensive LVH has also been clearly shown
by some authors as an important aetiological factor of HF-
PSF and the main pathophysiological factor for episodes of
decompensation [14].
Hormonal factors. The renin-angiotensin-aldesterone
system plays a central role in the development of LVH
[15]. Many experimental studies have demonstrated the
antitrophic role of angiotensin converting enzyme inhibitors
(ACE) or angiotensin II receptor blockers (ARBs) [16—18].
Other hormonal factors are involved: catecholamines,
insulin and growth hormone [19]. The antihypertensive
effect of some drugs in the spontaneously hypertensive rat
is associated with a reduction in heart weight only if the
haemodynamic effect is combined with a reduction in cat-
echolergic activity (which was not true with direct acting
vasodilators) [20].
Results of clinical trials
Impact of antihypertensive agents on LVH
Results of the first studies on regression of LVH in
hypertension were difficult to interpret because of some
methodological limitations [21,22]. The results of recent
comparative trials with good methodological quality [23]
partly contradict those of meta-analyses, which mostly con-
cluded that ACE and ARBs were superior to other drugs
[24]. The Prospective Randomized Enalapril Study Evaluat-
ing Regression of Ventricular Enlargement (PRESERVE) trial
showed no difference between enalapril and nifedipine [25].
The Left Ventricular hypertrophy regression Indapamide
versus Enalapril (LIVE) trial [26], which used a rigorous
methodology, with a sufficiently large number of patients
(200 patients per group), showed indapamide to be more
effective than enalapril on reducing left ventricular mass at
one year, with a comparable antihypertensive effect. The
largest LVH regression trial is the Losartan Intervention For
Endpoint reduction in hypertension (LIFE) trial [27], which
showed that, for a similar blood pressure control, losartan
(together with a diuretic in 90% of cases) produced a greater
LVH regression than atenolol (combined with a diuretic in the
same proportion of patients).
Consequences of LVH regression on prognosis
The incidence of cardiovascular complications appears to
be lower in patients whose LVH had regressed on treatment
than in those in whom LVH persists [28—31], but these tri-
als included small numbers of patients and do not establish
whether there was a parallel reduction in left ventricu-
lar mass and in cardiovascular risk. The lower incidence of
stroke with losartan in the LIFE trial was associated with a
364
greater LVH regression [32,33], although this difference may
be largely explained by a lower decrease in central blood
pressure by atenolol, as clearly shown in the Conduit Artery
Function Evaluation study (CAFE) trial [34].
Role of bilateral renal artery stenosis
Secondary hyperaldosteronism and volume overload,
related to a decrease of natriuresis, in case of significant
bilateral renal artery stenosis could explain the clinical
presentation of HF-PSF and particularly the recurrent
‘‘flash’’ acute pulmonary oedema. Revascularization in
this situation can prevent the recurrence of heart failure
decompensation [35,36]. This justifies to perform a renal
artery Doppler study, particularly if predisposing factors
for renal stenosis are present: severe systolic—diastolic
hypertension resistant to antihypertensive treatments,
age greater than 70 years old, multiple vascular lesions,
renal insufficiency, significant increase in plasma creatinine
after ACE or ARBs introduction. At the opposite, the role
of a unilateral renal stenosis in HF-PSF decompensation is
still discussed and angioplasty has not been shown to be
beneficial in this situation.
Role of myocardial ischaemia
Physiological relationship between ischaemia and
HF-PSF
In order to examine the relationship between left ventric-
ular diastolic dysfunction and myocardial ischaemia, two
questions need to be answered:
• is repeated or chronic myocardial ischaemia a factor
which initiates or predisposes to diastolic dysfunction?
• can an acute ischaemic episode be a factor that initiates
or predisposes to heart failure in a patient with diastolic
dysfunction?
In answer to the first question, we have to keep in mind
that left ventricular relaxation requires the active trans-
port of calcium into the sarcoplasmic reticulum, enabling
the dissociation of actin—myosin bridges. As a result of
hypoxia, which inhibits this dissociation process, ischaemia
can impaired active relaxation [37,38]. In addition, by
predisposing to cell necrosis and the development of inter-
stitial fibrosis, ischaemia contributes to the deterioration in
left ventricular structure and diastolic function. Ischaemia
can therefore reduce passive left ventricular compliance.
Myocardial ischemia could also be related to microcircula-
tory abnormalities, as found in hypertension and in diabetes
mellitus [39].
In order to answer the second question, many years ago,
acute myocardial ischaemia was shown to be involved in
the development of heart failure [40,41], and this is still
a current issue [42,43]. In 1987, a study demonstrated in 32
patients that all the echocardiographic diastolic parameters
were impaired in the first 15 s after coronary artery occlusion
[41]. In 2004, in a small study including 18 patients hospital-
ized for heart failure with left ventricular ejection fraction
(LVEF) greater or equal to 50%, a significant coronary artery
disease was found by coronary angiography in 39% of patients
and in 25% of cases, heart failure was associated with an
episode of myocardial ischaemia [43]. Finally, the extend of
P. de Groote et al.
coronary disease is associated with an increase in mortality
in patients with HF-PSF: findings from the coronary artery
surgery study (CASS) showed that in patients with HF-PSF,
the six-year mortality rate was 8% in the absence of coro-
nary artery disease, compared to 17% in the presence of a
significant single or double vessel disease and 32% in case of
triple vessel disease [44].
There are therefore arguments indicating that myocar-
dial ischaemia can contribute to diastolic dysfunction and
may be the cause of heart failure in a patient with diastolic
dysfunction.
Treatment of ischaemia and prevention of HF-PSF
and episodes of heart failure
Two questions must be answered to examine the relationship
between anti-ischaemic treatment and prognosis of HF-PSF:
• does anti-ischaemic treatment (pharmacological or revas-
cularization) in a patient without cardiac dysfunction
reduces the risk of HF-PSF?
• does anti-ischaemic treatment (pharmacological or by
revascularization) prevent heart failure decompensation
in a patient with HF-PSF?
To the best of our knowledge, no clinical trials have
answered to these two questions. We just have substud-
ies of different clinical trials and/or meta-analyses without
any information about the type of heart failure assessed.
While the treatment of coronary risk factors, particularly
the treatment of hypertension, reduces the risk of heart fail-
ure, anti-ischaemic treatment does not appear to reduce the
incidence of heart failure [45,46]. In the meta-analysis of
the Blood Pressure Lowering Treatment Trialists’ collabora-
tion (BPLTT) [46], beta-blockers were not superior to ACE in
preventing heart failure. However, calcium channel block-
ers appeared to be less effective than ACE, but also less
effective than diuretics and beta-blockers in preventing the
development of heart failure.
In the Occluded Artery Trial (OAT), desocclusion of a coro-
nary artery by angioplasty did not reduce the risk of heart
failure [47]. Furthermore, angioplasty of an occluded artery
had no effect on prognosis, whether or not the patients had
previous heart failure and whether or not they had LVEF less
than 50%.
A study published in 2000 examined the findings from
46 patients hospitalized for rapidly resolving acute pul-
monary oedema (‘‘flash’’ oedema) [45]. Twenty-seven of
these patients (58%) had LVEF greater than 40%, 38 (82%)
underwent coronary angiography and among these, 33 (86%)
had a significant coronary artery disease. Nineteen of these
33 patients underwent bypass surgery and eight a coronary
angioplasty. During the three-year of the follow-up period,
pulmonary oedema recurred in half of the patients, and
in nine patients (47%) of the 19 who were revascularized.
Despite its major limitations (small number of patients and
lack of randomization), this study suggests that coronary
revascularization has no preventive effect on the devel-
opment of pulmonary oedema in patients with preserved
systolic function and a past history of pulmonary oedema.
Finally, the ACC/AHA 2001 guidelines for the manage-
ment of HF-PSF state that ‘‘coronary revascularization is
recommended in patients with coronary artery disease in
whom symptomatic or demonstrable myocardial ischaemia
Treatment of heart failure with preserved systolic function
is judged to have an adverse effect on diastolic function’’
although with a level of evidence of C [48]. This proposal
is based on pathophysiological reasoning but not on clinical
evidence. In 2005, the European and American guidelines
for the management of heart failure both stated that there
was a strong evidence to perform coronary revascularization
only to patients with angina and not to patients with asymp-
tomatic coronary disease [49,50]. They did not recommend
coronary revascularization in order to improve ventricular
function or to reduce symptoms of heart failure [51].
Role of supraventricular arrhythmias
Supraventricular arrhythmias are considered to have an
adverse effect in HF-PSF. Tachycardia, which reduces the
duration of diastole, and the loss of atrial systole con-
siderably decrease cardiac output. LVH increases these
abnormalities. In experimental studies in dogs, sinus tachy-
cardia in the presence of LVH rapidly increases left atrial
pressure [52]. The theoretical treatment of choice to control
heart rate is beta-blockers, which also reduce myocardial
ischaemia and blood pressure. Non-dihydropyridine calcium
blockers and/or digoxin, particularly in case of atrial fibrilla-
tion, are an alternative to beta-blockers. The ideal situation
is to obtain a heart rate close to 70 per minute and in
any case lower than 90 per minute. Atrial ventricular node
ablation with pacemaker implantation is rarely required.
Atrial fibrillation ablation may be useful in case of recurrent
heart failure decompensations. Finally, the role of ivabra-
dine in controlling heart rate in patients with sinus rhythm
is unknown in HF-PSF.
Other triggering factors
Heart failure decompensation may be promoted by extrac-
ardiac factors such as non compliance to the low sodium
diet or to medical treatment, intake of non-recommended
drugs (particularly non-steroidal anti-inflammatory drugs,
rich sodium drugs, etc.), pulmonary infection or any other
infection and anemia. These extracardiac factors are not
specific to HF-PSF but also affect heart failure with systolic
dysfunction.
Data from registers and controlled trials
on the pharmacological management of
HF-PSF
Specific features of HF-PSF
As described in the introduction, the treatment of HF-PSF is
currently based on our pathophysiological knowledge. The
main goal of the treatment is to reduce the left ventricular
end-diastolic pressure.
By avoiding salt and water retention, diuretics are the
treatment of choice for this disease. However, as in heart
failure with systolic dysfunction, no study has assessed their
benefit in HF-PSF. With nitrates, diuretics are effective in the
management of acute episodes. In chronic stable patients,
the minimal doses of diuretics will be prescribed, partic-
ularly in the elderly, in order to control symptoms and to
365
reduce the risk of dehydration. In HP-PSP, the adaptive possi-
bility of the heart is decreased, related to a steeper diastolic
pressure—volume curve. Minor changes in volume are asso-
ciated with large changes in pressure (a moderate increase
in volume increases the risk of decompensation, and in con-
trast, a small reduction in ventricular volume predisposes to
hypotension).
Heart rate plays an important role in the increase of
diastolic pressures. Alongside diuretics, nitrates and beta-
blockers, calcium channel blockers slowing heart rate can
be used. Finally, theoretically, renin-angiotensin system
inhibitors are useful in the management of these patients:
they control blood pressure, reduce left ventricular mass
and may improve diastolic function [53].
Epidemiological studies
Several observational epidemiological studies have exam-
ined the numbers of prescriptions of different classes of
drugs. In some of these studies, the authors examine the
impact of various drugs on morbidity and mortality. These
studies are not randomized trials and all of these analyses
were conducted retrospectively. Nevertheless, they provide
useful information on the therapeutic management of HF-
PSF.
An important initial finding from these registries is the
relatively limited use of LVEF measurement in patients
hospitalized for acute heart failure. In American studies
[54—57], LVEF measurement was performed in approx-
imately 50—60% of the patients, at the exception of
one study, the Organized Program to Initiate Lifesav-
ing Treatment in Hospitalized Patients With Heart Failure
(OPTIMIZE-HF) trial [58] where LVEF was measured in 85% of
the patients. In Europe, LVEF is measured in almost 80% of
patients [59,60].
Prescription rates for the different classes of drugs
Prescription rates of the different classes of drugs from
some epidemiological studies are summarized in Table 1.
Most of these studies involved patients admitted in hospitals
for heart failure decompensation. Shamagian et al. divided
their Spanish population into three groups depending on the
year of hospitalization [60]. The study, from the Cardiovas-
cular Health Study, examined the general population over
65 years old with ambulatory HF-PSF. In the Berry study,
diuretic and ACE prescription rates should be interpreted
with caution as these drugs were one of the inclusion criteria
[59].
In some studies, the authors compared the type of man-
agement according to the severity of LV dysfunction. In the
Management to Improve Survival in Congestive Heart Fail-
ure (MISCHF) register, the 1291 patients were divided into
three subgroups depending on LVEF function: less or equal
to 39%, 40 to 50%, and greater than 50% [55]. In the major-
ity of cases, ACE were being prescribed more commonly in
patients with systolic dysfunction, both on admission and
at discharge from hospital. The doses of ACE were also
higher in systolic dysfunction [55]. Similar results were found
in the EuroHeart Failure survey [62,63]. The same finding
also applies to beta-blockers in the most recent analyses
[57,63].
 366
Table 1 Prescription rates of different classes of drugs in epidemiological studies.
n Date LVEF (%) Diur (%) ACE (%) ARBs (%) BB (%) Spir (%) Ca-B (%) Digo (%)
CHS 170 1989—1993 ≥ 55 59 25 17 31 41
REP 91 59 1991 ≥ 50 78 31 19 24 27
Alabama 238 1994 ≥ 40 30 31 47
MISCHF 312 1995—1997 ≥ 50 59 29 23 39 30
76 45 19 43 36
Smith et al. 200 1996—1998 ≥ 40 79 34 19 50 30
Berry 130 2000 ≥ 40 95 65 38 12 24 23
Spanish 147 1991—1996 ≥ 50 64 42 0 12 10 18 39
Study 109 1997—1999 69 55 5 12 5 30 22
186 2000—2001 64 49 6 28 12 36 16
EuroHeart 3,148 2000—2001 ≥ 40 85 58 4 39 17 28 31
Failure
Dobre 443 2000—2005 ≥ 40 88 66 12 51 41 15 22
FOCALE 245 ? ≥ 45 67 53 16 34 16 12 19
REP 03 306 2003—2005 ≥ 50 24 17 21
71 51 63
ADHERE 26,322 2004 ≥ 40 65 36 13 46 5 19
80 47 13 52 11 21
LVEF: left ventricular ejection fraction; Diur: diuretics; ACE: angiotensin II converting enzyme inhibitors; ARBs: angiotensin II receptor blockers; BB: beta-blockers; Spir: spironolactone:
CaB: calcium channel blockers; Digo: digoxin.
For the trials by Smith et al., Berry et al., Dobre et al. and the Spanish trial, treatment was at discharge from hospital. The second line in the MISCHG, REP 03 and ADHERE studies is
treatment at discharge from hospital. The FOCALE trial randomized ambulatory patients over 65 years old with an ECG and echocardiogram at inclusion.
CHS, [61]; REP91, [54]; Alabama, [65]; MISCH, [55]; Smith et al., [82]; Berry et al., [59]; Spanish trial, [60]; EuroHeart Failure Survey, [63]; Dobre et al., [66]; FOCALE, [81]; REP 03, [64];
ADHERE, [57].

P. de Groote et al.
Treatment of heart failure with preserved systolic function
In other studies, prescription rates of different drugs
before hospitalization and at discharge have been exam-
ined [55,57,64]. Diuretics were the most widely prescribed
drugs in these studies, followed by the ACE, with an increase
in their prescription rates during the hospitalization. How-
ever, we do not know whether this approach was guided by
blood pressure level. The prescribing rate of beta-blockers
also appears to increase in the studies conducted after 2000
whereas digoxin prescription decreased, from 40% in the
1990s to 20% after 2000. Prescription rate of calcium chan-
nel blockers remains relatively stable with no information
available about the type of calcium blocker (vasodilators or
bradycardiac agents).
Relationship between treatments and
morbidity—mortality rates
Because of some contradictory results of different retro-
spective studies from registries, it is difficult to draw any
conclusions.
An analysis of a population from the American MEDICARE
system including 1091 patients over 65 years old, hospital-
ized in 1994 for heart failure did not show any relationship
between the prescription of ACE and four-year survival
in the 238 patients with LVEF greater and equal to 40%
[65].
In the MISCHF register, ACE prescription was associated
with a shorter length of hospitalization and a 60% reduc-
tion in the six months mortality rate in patients with LVEF
between 40 and 49%. Conversely, prescription of ACE in the
subgroup of patients with LVEF greater or equal to 50% was
associated with a 30% non-significant decrease in morbid-
ity and mortality [55]. The power of this analysis is limited
by the small number of patients per subgroups (less than
200).
In the Spanish study, authors compared mortality of their
patients admitted for heart failure decompensation with
a separate analysis over three different inclusion periods
[60]. Annual mortality was similar during the three periods,
between 9 to 12%. By multivariate analysis, the prescription
of ACE or of an ARBs was associated with a greater survival
rate (36% mortality reduction). On the other hand, digoxin
was associated with a 40% significant increase in mortality.
In the Dutch study [66], prescription of beta-blockers was
associated with a significant reduction in mortality, with an
adjusted relative risk of 0.57 [0.37—0.88, p = 0.01], with a
dose effect. It is interesting to note that in this study, digoxin
prescription was also associated with an excess mortality
(adjusted RR = 1.58 [1.006—2.47, p = 0.05]).
The ACE and beta-blockers were also found to have a
beneficial effect in the EuroHeart Failure Study [63]. After
12-week of follow-up, prescription of ACE and of beta-
blockers were associated with a 45% (RR = 0.55 [0.43—0.71])
and with a 39% (RR = 0.61 [0.48—0.77]) reduction in total
mortality, respectively.
Clinical trials
Small studies and retrospective analyses
A few small studies (with less than 400 patients) have
assessed the effect of different classes of treatment in HF-
PSF.
367
The open study by Aronow et al. assessed the effect of
a beta-blocker, propanolol (90 mg/d), on prognosis in 158
patients, aged 81 ± 8 years old, in class II-III NYHA with
LVEF greater or equal to 40% and a history of myocardial
infarction [67]. All the patients were receiving diuretics
and ACE for at least two months. Total mortality after 32-
months of follow-up was reduced by 35% with propanolol
(44 deaths compared to 60, p = 0.007) and total mortality
and non-fatal myocardial infarction were reduced by 37%
(p = 0.002).
The Survival of Myocardial Infarction Long-Term Evalu-
ation study (SMILE-ISCHEMIA study) examined zofenopril in
303 patients admitted with myocardial infarction and LVEF
greater than 40% [68]. The primary objective of the study
was to examine the effect of zofenopril on the extent of
myocardial ischemic burden (studied by a 24 h Holter moni-
toring and by an exercise test) after six months of treatment.
The study demonstrated a significant reduction of the pri-
mary objective with zofenopril. There were only two deaths
during the follow-up period and heart failure developed or
worsened in 12 patients: all except for one of these were on
placebo.
A retrospective analysis of the European Trial on Reduc-
tion of Cardiac Events with perindopril in stable coronary
artery disease study (EUROPA) was conducted in patients
with LVEF greater than 40% [69]. The EUROPA study was
a double-blind, randomized, placebo controlled trial of an
ACE, perindopril (8 mg/d), in 12,218 patients with coronary
artery disease but without clinical evidence of heart failure.
LVEF was measured in 58% of the population, of whom 6,878
patients (56%) had LVEF greater than 40%. Perindopril sig-
nificantly reduced the incidence of the primary end point
(cardiovascular mortality, non-fatal myocardial infarction
and resuscitated sudden death) from 9.8 to 8.3% (RR = 0.84
[0.77—0.98]).
Large-scale trials
Four randomized, placebo-controlled, multicenter trials
have examined the effects of different pharmacological
treatments in HF-PSF: the DIG, CHARM-preserved, PEP-CHF
and SENIORS trials.
The major therapeutic characteristics of these trials are
summarized in Table 2. Diuretics were still the most com-
monly prescribed class of drugs, followed by beta- blockers
in the two most recent studies. ACE were widely pre-
scribed in the DIG trial and digoxin prescription was variable,
between 12 and 40%, in the three other trials.
Digitalis Intervention Group (DIG trial)
The DIG trial can be considered to be the first random-
ized multicenter trial in HF-PSF. A subgroup of 988 North
American patients with a LVEF greater than 45% was ran-
domized to receive digoxin (492 patients) or placebo (496
patients). Digoxin had no impact on total or cardiovascular
mortality, mortality from heart failure or on the majority
of the combined end-points. Hospitalizations for heart fail-
ure were significantly reduced with digoxin but only after
two-year of follow-up and this difference was not significant
at the end of the trial. There was a trend towards more
hospitalization for unstable angina in patients on digoxin
[70].
368
Table 2 Prescription rates of different classes of drugs in the 4 randomized trials in HF-PSF.
n Date LVEF (%) Diur (%)
DIG 988 1991—1993 ≥ 45 76
CHARM 3,023 1999—2000 ≥ 40 75
SENIORS 2,135 2000—2002 86
PEP-CHF 850 2000—2003 ≥ 40 46
55a
LVEF: left ventricular ejection fraction; Diur: diuretics; ACE: angiotensin II converting enzyme inhibitors; ARBs: angiotensin II receptor
blockers; BB: beta-blockers; Spir: spironolactone; CaB: calcium channel blockers; Digo: digoxin.
a Including thiazides.
Candesartan in Heart Failure Assessment of Reduction
in Mortality and Morbidity-Preserved study (CHARM-
preserved study)
This is to date the largest trial in terms of number of
patients, which examine the effects of an ARBs, the can-
desartan in HF-PSF [71]. CHARM-preserved trial included
3023 patients older than 18 years, with NYHA class II-IV
clinical heart failure who had been hospitalized at least
once for a cardiac cause and had an LVEF greater than 40%.
Patients were randomized double-blind against placebo. The
primary objective was to examine the effect of candesartan
on cardiovascular mortality and hospitalizations for heart
failure. After 36.6-months of follow-up, candesartan had not
reduced the incidence of the primary end point (22% versus
24% with a 11% non-significant reduction on candesartan).
Candesartan had no impact on the different secondary end
points (hospitalization for heart failure, myocardial infarc-
tion, stroke or coronary revascularization). The average
dose of candesartan at six months was 25 mg/d. There were
significantly more adverse effects on candesartan than on
placebo: more hypotension (2.4% versus 1.1%), more hyper-
kalaemia (1.5% versus 0.6%) and a greater rise in serum
creatinine (4.8% versus 2.4%).
Despite this statistically negative result, the CHARM trial
shows that a large scale randomized trial can be conducted
in this complex disease. This study opened the way for new
trials in HF-PSF.
Study of the Effect of Nebivolol Intervention on Out-
comes and Rehospitalization in Seniors With Heart
Failure trial (SENIORS trial)
The SENIORS trial cannot be considered to be a specific
trial of HF-PSF because HF-PSF patients only represented a
subgroup of the total population and because the LVEF cut-
off value defining HF-PSF was unusually low (LVEF greater
than 35%) [72]. The aim of the trial was to examine the
effect of a beta-blocker, nebivolol, in 2135 patients over
70 years, who had either been hospitalized within the pre-
vious year for heart failure or in whom an LVEF of less or
equal to 35% had been found within the previous six months.
The major end-point was total mortality and hospitaliza-
tions for a cardiovascular cause. After a follow-up period
of 21 months, nebivolol produced a significant 14% reduc-
tion in the incidence of the primary end-point (31.1% versus
35.3%, p = 0.04). Median LVEF was 34%, although only 20% of
the population had an LVEF greater than 40%. The effect of
Nebivolol on the primary end-point was similar whether the
LVEF was over or under 35%.
P. de Groote et al.
ACE (%) ARBs (%) BB (%) Spir (%) CaB (%) Digo (%)
86 8
19 56 12 32 28
83 7 28 11 40
55 10 33 12
Perindopril in Elderly People — Congestive Heart Fail-
ure trial (PEP-CHF)
The PEP-CHF trial examined the effect of an ACE, perindo-
pril 4 mg/d, on morbidity and mortality in elderly patients
followed up for HF-PSF [73]. The inclusion criteria were
age greater or equal to 70 years, heart failure treated with
diuretics, with a LVEF greater than 40%. In addition, three
out of nine clinical criteria for heart failure and two out
of four echocardiographic criteria for diastolic dysfunction
were required. The average age was 75 years and 55% of
the patients were women, 79% were hypertensive and 26%
had a past history of myocardial infarction. The primary
end-point was total mortality and hospitalizations for heart
failure at one year. The trial showed a non-significant impact
of perindopril on the primary end point. The annual event
rate was 12.2% in the perindopril subgroup and 13.2% in the
placebo subgroup. At the end of the trial, event rates were
23.6 and 25.1%, respectively. Similar results were found
with all the secondary end points: total or cardiovascular
mortality, hospitalizations for heart failure, duration of hos-
pitalizations, increase in treatment.
These results are difficult to interpret because of numer-
ous problems. The inclusion period, as well as the follow-up
period, were extended in order to obtain a sufficient number
of events. The drop-out rate was relatively high, 40% in the
perindopril group and 36% in the placebo group. Open label
ACE was prescribed in 35% of the patients in the perindopril
arm and in 37% in the placebo arm.
In summary, these trials did not show any significant
effect of different classes of drugs studies, digoxin, ACE or
ARBs, except for a beta-blocker (nebivolol) in a non-specific
HF-PSF study.
Two other randomized trials are ongoing: one, the Irbe-
sartan in Heart Failure With Preserved Systolic Function trial
(I-PRESERVE) [74] is assessing irbesartan and the other, the
trial of aldosterone antagonist therapy in adults with pre-
served ejection fraction congestive heart failure (TOPCAT
trial) is assessing an aldosterone receptor blocker, spirono-
lactone. The results of these two trials will perhaps enable
us to improve the management of patients suffering from
HF-PSF.
Special features of elderly patients over 80
years old
The prevalence of HF-PSF increases with age. The diagno-
sis in octogenarians is often difficult because of atypical
Treatment of heart failure with preserved systolic function
symptoms [75]. In addition, some non-specific ‘‘geriatric’’
signs (asthenia, confusion, behavioral disorders, fall, loss
of independence) can also be the only clinical feature of
heart failure, which is responsible for a delay in diagnosis
and treatment. The clinical presentation is even more atyp-
ical and the prognosis even poorer if the heart failure occurs
in frail patients with several comorbidities. Epidemiological
data from a register of 86,094 institutionalized 85-year-old
patients with heart failure [76] indicate that one third of
the patients had at least six comorbidities in addition to
heart failure, with a higher prevalence of cognitive disor-
ders (57% of cases). In the Euro Heart Failure Survey I [77],
infection was present in 42% of patients over 80 years old,
confusion in 23%, anemia in 23% and severe renal failure
(creatinine clearance less than 30 ml/min) in 15%. The pres-
ence of these comorbidities implies geriatric management in
order to identify markers of ‘‘fragility’’ in the elderly (cogni-
tive problems, walking disorders, depression, malnutrition,
social isolation, loss of independence etc.) [78].
Cardiovascular disease is more serious in the elderly. In
the Euro Heart Failure Survey I registry, total mortality at
12 weeks in patients with HF-PSF was significantly higher
in octogenarians (average age 85 years old) compared to
younger patients (average age 69 years old) (17% versus 7%,
p < 0.0001) [77]. The excess mortality was due to both car-
diovascular and non-cardiovascular causes. Because of this,
it may be useful to consider the best end-points to be used in
this population in future clinical trials: mortality, cardiovas-
cular events, rehospitalisation, quality of life? In practice,
the therapeutic management for each patient must be based
not on actual age but on an individual assessment taking
into account the ‘‘geriatric evaluation’’ of the elderly (life
expectancy, quality of life, comorbidities, frailty, iatrogenic
risk, etc.) [78].
Educational program
Few studies have assessed the effect of multidisciplinary
management in patients with HF-PSF. Interpretation of the
results of theses studies are therefore difficult but the effect
of multidisciplinary management appears to be less effec-
tive than in patients with systolic dysfunction.
It is possible that studies demonstrating a benefit of
multidisciplinary management in terms of morbidity and
mortality have included patients with HP-FSP, although no
analysis by type of dysfunction was available until the pub-
lication by Galbreath et al. [79]. These authors randomized
1069 patients with heart failure and compared multidis-
ciplinary follow-up with telephone calls and education to
conventional follow up for 18 months. Seventy per cent of
patients had systolic dysfunction and 30% had HF-PSF. This
study demonstrated a significant reduction in mortality and
cardiovascular events in the group of patients with systolic
dysfunction whereas no significant effect was found in the
subgroup of patients with HF-PSF. Multidisciplinary manage-
ment in this study had little impact on blood pressure and
this subgroup of patients appeared to be at lower risk.
In terms of effect on quality of life, this may be more
significant although again there are insufficient studies
available. One study conducted in 32 women with NYHA
class II or III and LVEF greater than 45%, randomized to 12
weeks of mild to moderate regular physical exercise asso-
369
ciated with therapeutic education compared to therapeutic
education alone showed significant improvement in walk-
ing tolerance, quality of life and depression indices in the
intervention group [80].
Therapeutic education and multidisciplinary manage-
ment in patients with HF-PSF is probably more useful in
controlling etiological and precipitating factors than in
terms of preventing decompensation and reducing mortal-
ity. Therefore, the influence of therapeutic education is
undoubtedly involved in the beginning of the disease. Deteri-
oration in diastolic function often precedes the development
of the initial symptoms by several years and early diagnosis
and treatment of these abnormalities are essential in order
to prevent irreversible damages. Primary prevention of HF-
PSF requires smoking cessation and drastic control of blood
pressure, hypercholesterolaemia and all other risk factors
for coronary artery disease.
As for systolic dysfunction, changes in lifestyle are essen-
tial and must be combined with an appropriate diet with
low sodium and alcohol intake and physical activity must
be maintained. Weight monitoring and control of conges-
tive signs are important but often difficult as exacerbations
of left heart failure are usually sudden and more rarely
preceded by warning signs (reduced walking tolerance,
arrhythmia, increase of blood pressure, infection etc.).
Knowledge of these warning signs however remains essential
and patients must be educated about them.
Conclusions
The therapeutic management of patients with HF-PSF is dif-
ficult. The lack of clear results from the few randomized
trials in this disease does not help us in its management. This
management is based on our pathophysiology knowledge
of HF-PSF which is multifactorial, involving hypertension,
myocardial ischaemia, intrinsic myocardial damage and con-
comitant diseases (diabetes, renal failure). In the absence
of significant results of large therapeutic trials, treatment
of HF-PSF is therefore based on patient education and con-
trol of salt and water retention, blood pressure, heart rate
and episodes of myocardial ischaemia.
References
[1] Juilliere Y, Trochu JN, de Groote P, et al. Heart failure with pre-
served systolic function: a diagnostic algorithm for a pragmatic
definition. Arch Mal Coeur Vaiss 2006;99:279—86.
[2] Paulus WJ, Tschope C, Sanderson JE, et al. How to diagnose
diastolic heart failure: a consensus statement on the diagnosis
of heart failure with normal left ventricular ejection frac-
tion by the Heart Failure and Echocardiography Associations
of the European Society of Cardiology. Eur Heart J 2007;28:
2539—50.
[3] Kitzman DW, Higginbotham MB, Cobb FR, Sheikh KH, Sulli-
van MJ. Exercise intolerance in patients with heart failure
and preserved left ventricular systolic function: failure of the
Frank-Starling mechanism. J Am Coll Cardiol 1991;17:1065—72.
[4] Mosterd A, D’Agostino RB, Silbershatz H, et al. Trends in the
prevalence of hypertension, antihypertensive therapy, and left
ventricular hypertrophy from 1950 to 1989. N Engl J Med
1999;340:1221—7.
370
[5] Kannel WB, Gordon T, Offutt D. Left ventricular hyper-
trophy by electrocardiogram. Prevalence, incidence, and
mortality in the Framingham study. Ann Intern Med 1969;71:
89—105.
[6] Cuspidi C, Lonati L, Sampieri L, et al. Impact of blood pressure
control on prevalence of left ventricular hypertrophy in treated
hypertensive patients. Cardiology 2000;93:149—54.
[7] Schmieder RE, Messerli FH, Garavaglia GE, Nunez BD. Dietary
salt intake. A determinant of cardiac involvement in essential
hypertension. Circulation 1988;78:951—6.
[8] Manolio TA, Levy D, Garrison RJ, Castelli WP, Kannel WB. Rela-
tion of alcohol intake to left ventricular mass: The Framingham
Study. J Am Coll Cardiol 1991;17:717—21.
[9] Garavaglia GE, Messerli FH, Schmieder RE, Nunez BD, Oren S.
Sex differences in cardiac adaptation to essential hyperten-
sion. Eur Heart J 1989;10:1110—4.
[10] Kupari M, Koskinen P, Virolainen J. Correlates of left ven-
tricular mass in a population sample aged 36 to 37 years.
Focus on lifestyle and salt intake. Circulation 1994;89:
1041—50.
[11] Ravogli A, Trazzi S, Villani A, et al. Early 24-hour blood pressure
elevation in normotensive subjects with parental hypertension.
Hypertension 1990;16:491—7.
[12] Koren MJ, Mensah GA, Blake J, Laragh JH, Devereux RB. Com-
parison of left ventricular mass and geometry in black and
white patients with essential hypertension. Am J Hypertens
1993;6:815—23.
[13] Esposito G, Rapacciuolo A, Naga Prasad SV, et al. Genetic
alterations that inhibit in vivo pressure-overload hypertrophy
prevent cardiac dysfunction despite increased wall stress. Cir-
culation 2002;105:85—92.
[14] Haider AW, Larson MG, Franklin SS, Levy D. Systolic blood pres-
sure, diastolic blood pressure, and pulse pressure as predictors
of risk for congestive heart failure in the Framingham Heart
Study. Ann Intern Med 2003;138:10—6.
[15] Dahlof B. Factors involved in the pathogenesis of hyperten-
sive cardiovascular hypertrophy A review. Drugs 1988;35(Suppl
5):6—26.
[16] Kaneko K, Susic D, Nunez E, Frohlich ED. ACE inhibition reduces
left ventricular mass independent of pressure without affecting
coronary flow and flow reserve in spontaneously hypertensive
rats. Am J Med Sci 1997;314:21—7.
[17] Nagano M, Higaki J, Mikami H, et al. Converting enzyme
inhibitors regressed cardiac hypertrophy and reduced tissue
angiotensin II in spontaneously hypertensive rats. J Hypertens
1991;9:595—9.
[18] Sabri A, Samuel JL, Marotte F, Poitevin P, Rappaport L, Levy BI.
Microvasculature in angiotensin II-dependent cardiac hypertro-
phy in the rat. Hypertension 1998;32:371—5.
[19] Weber KT, Sun Y, Guarda E. Structural remodeling in hyper-
tensive heart disease and the role of hormones. Hypertension
1994;23:869—77.
[20] Sen S, Tarazi RC, Bumpus FM. Cardiac hypertrophy and antihy-
pertensive therapy. Cardiovasc Res 1977;11:427—33.
[21] Gottdiener JS, Reda DJ, Massie BM, Materson BJ, Williams DW,
Anderson RJ, The Department of Veterans Affairs Cooperative
Study Group on Antihypertensive Agents. Effect of single-drug
therapy on reduction of left ventricular mass in mild to moder-
ate hypertension: comparison of six antihypertensive agents.
Circulation 1997;95:2007—14.
[22] Liebson PR, Grandits GA, Dianzumba S, et al. Comparison of
five antihypertensive monotherapies and placebo for change in
left ventricular mass in patients receiving nutritional-hygienic
therapy in the Treatment of Mild Hypertension Study (TOMHS).
Circulation 1995;91:698—706.
[23] Gosse P, Dubourg O, Gueret P. Regression of left ventricular
hypertrophy with echocardiography: some lessons from the
LIVE study. J Hypertens 2003;21:217—21.
P. de Groote et al.
[24] Klingbeil AU, Schneider M, Martus P, Messerli FH, Schmieder RE.
A meta-analysis of the effects of treatment on left ventricular
mass in essential hypertension. Am J Med 2003;115:41—6.
[25] Devereux RB, Palmieri V, Sharpe N, et al. Effects of once-daily
angiotensin-converting enzyme inhibition and calcium channel
blockade-based antihypertensive treatment regimens on left
ventricular hypertrophy and diastolic filling in hypertension:
the prospective randomized enalapril study evaluating regres-
sion of ventricular enlargement (PRESERVE) trial. Circulation
2001;104:1248—54.
[26] Gosse P, Sheridan DJ, Zannad F, et al. Regression of left ven-
tricular hypertrophy in hypertensive patients treated with
indapamide SR 1.5 mg versus enalapril 20 mg: the LIVE study. J
Hypertens 2000;18:1465—75.
[27] Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular
morbidity and mortality in the Losartan Intervention For End-
point reduction in hypertension study (LIFE): a randomised trial
against atenolol. Lancet 2002;359:995—1003.
[28] Muiesan ML, Salvetti M, Rizzoni D, Castellano M, Donato F,
Agabiti-Rosei E. Association of change in left ventricular mass
with prognosis during long-term antihypertensive treatment. J
Hypertens 1995;13:1091—5.
[29] Yurenev AP, Dyakonova HG, Novikov ID, et al. Management of
essential hypertension in patients with different degrees of
left ventricular hypertrophy. Multicenter trial. Am J Hypertens
1992;5:182S—9S.
[30] Verdecchia P, Schillaci G, Borgioni C, et al. Prognostic signif-
icance of serial changes in left ventricular mass in essential
hypertension. Circulation 1998;97:48—54.
[31] Cipriano C, Gosse P, Bemurat L, et al. Prognostic value of
left ventricular mass and its evolution during treatment in
the Bordeaux cohort of hypertensive patients. Am J Hypertens
2001;14:524—9.
[32] Devereux RB, Dahlof B, Gerdts E, et al. Regression of hyper-
tensive left ventricular hypertrophy by losartan compared with
atenolol: the Losartan Intervention for Endpoint Reduction in
Hypertension (LIFE) trial. Circulation 2004;110:1456—62.
[33] Devereux RB, Wachtell K, Gerdts E, et al. Prognostic signif-
icance of left ventricular mass change during treatment of
hypertension. JAMA 2004;292:2350—6.
[34] Williams B, Lacy PS, Thom SM, et al. Differential impact of
blood pressure-lowering drugs on central aortic pressure and
clinical outcomes: principal results of the Conduit Artery Func-
tion Evaluation (CAFE) study. Circulation 2006;113:1213—25.
[35] Pickering TG, Herman L, Devereux RB, et al. Recurrent pul-
monary oedema in hypertension due to bilateral renal artery
stenosis: treatment by angioplasty or surgical revascularisa-
tion. Lancet 1988;2:551—2.
[36] Bloch MJ, Trost DW, Pickering TG, Sos TA, August P. Prevention
of recurrent pulmonary edema in patients with bilateral ren-
ovascular disease through renal artery stent placement. Am J
Hypertens 1999;12:1—7.
[37] Nayler WG, Poole-Wilson PA, Williams A. Hypoxia and calcium.
J Mol Cell Cardiol 1979;11:683—706.
[38] Mahmarian JJ, Pratt CM. Silent myocardial ischemia in patients
with coronary artery disease. Possible links with diastolic left
ventricular dysfunction. Circulation 1990;81:III33—40.
[39] Galderisi M, Cicala S, Caso P, et al. Coronary flow reserve and
myocardial diastolic dysfunction in arterial hypertension. Am
J Cardiol 2002;90:860—4.
[40] Clark LT, Garfein OB, Dwyer Jr EM. Acute pulmonary edema
due to ischemic heart disease without accompanying myocar-
dial infarction. Natural history and clinical profile. Am J Med
1983;75:332—6.
[41] Labovitz AJ, Lewen MK, Kern M, Vandormael M, Deligonal U,
Kennedy HL. Evaluation of left ventricular systolic and diastolic
dysfunction during transient myocardial ischemia produced by
angioplasty. J Am Coll Cardiol 1987;10:748—55.
Treatment of heart failure with preserved systolic function
[42] Bogaty P, Mure P, Dumesnil JG. New insights into diastolic
dysfunction as the cause of acute left-sided heart failure
associated with systemic hypertension and/or coronary artery
disease. Am J Cardiol 2002;89:341—5.
[43] Arques S, Ambrosi P, Gelisse R, Roux E, Lambert M, Habib G.
Prevalence of angiographic coronary artery disease in patients
hospitalized for acute diastolic heart failure without clinical
and electrocardiographic evidence of myocardial ischemia on
admission. Am J Cardiol 2004;94:133—5.
[44] Judge KW, Pawitan Y, Caldwell J, Gersh BJ, Kennedy JW. Con-
gestive heart failure symptoms in patients with preserved left
ventricular systolic function: analysis of the CASS registry. J Am
Coll Cardiol 1991;18:377—82.
[45] Kramer K, Kirkman P, Kitzman D, Little WC. Flash pul-
monary edema: association with hypertension and reoc-
currence despite coronary revascularization. Am Heart J
2000;140:451—5.
[46] Turnbull F, Blood Pressure Lowering Treatment Trialists’ Col-
laboration. Effects of different blood-pressure-lowering
regimens on major cardiovascular events: results of
prospectively-designed overviews of randomised trials.
Lancet 2003;362:1527—35.
[47] Hochman JS, Lamas GA, Buller CE, et al. Coronary intervention
for persistent occlusion after myocardial infarction. N Engl J
Med 2006;355:2395—407.
[48] Hunt SA, Baker DW, Chin MH, et al. ACC/AHA guidelines for
the evaluation and management of chronic heart failure in the
adult: executive summary. A report of the American College of
Cardiology/American Heart Association Task Force on Practice
Guidelines (Committee to revise the 1995 Guidelines for the
Evaluation and Management of Heart Failure). J Am Coll Cardiol
2001;38:2101—13.
[49] Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 Guide-
line Update for the Diagnosis and Management of Chronic
Heart Failure in the Adult: a report of the American Col-
lege of Cardiology/American Heart Association Task Force on
Practice Guidelines (Writing Committee to Update the 2001
Guidelines for the Evaluation and Management of Heart Fail-
ure): developed in collaboration with the American College of
Chest Physicians and the International Society for Heart and
Lung Transplantation: endorsed by the Heart Rhythm Society.
Circulation 2005;112:e154—235.
[50] Swedberg K, Cleland J, Dargie H, et al. Guidelines for the
diagnosis and treatment of chronic heart failure: executive
summary (update 2005): The Task Force for the Diagnosis and
Treatment of Chronic Heart Failure of the European Society of
Cardiology. Eur Heart J 2005;26:1115—40.
[51] McMurray J, Swedberg K. Treatment of chronic heart fail-
ure: a comparison between the major guidelines. Eur Heart
J 2006;27:1773—7.
[52] Berger RD, Wolff MR, Anderson JH, Kass DA. Role of atrial con-
traction in diastolic pressure elevation induced by rapid pacing
of hypertrophied canine ventricle. Circ Res 1995;77:163—73.
[53] Friedrich SP, Lorell BH, Rousseau MF, et al. Intracardiac
angiotensin-converting enzyme inhibition improves diastolic
function in patients with left ventricular hypertrophy due to
aortic stenosis. Circulation 1994;90:2761—71.
[54] Senni M, Tribouilloy CM, Rodeheffer RJ, et al. Congestive
heart failure in the community: a study of all incident cases
in Olmsted County, Minnesota, in 1991. Circulation 1998;98:
2282—9.
[55] Philbin EF, Rocco Jr TA, Lindenmuth NW, Ulrich K, Jenkins PL.
Systolic versus diastolic heart failure in community practice:
clinical features, outcomes, and the use of angiotensin-
converting enzyme inhibitors. Am J Med 2000;109:605—13.
[56] Masoudi FA, Havranek EP, Smith G, et al. Gender, age, and heart
failure with preserved left ventricular systolic function. J Am
Coll Cardiol 2003;41:217—23.
371
[57] Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC.
Clinical presentation, management, and in-hospital outcomes
of patients admitted with acute decompensated heart fail-
ure with preserved systolic function: a report from the Acute
Decompensated Heart Failure National Registry (ADHERE)
Database. J Am Coll Cardiol 2006;47:76—84.
[58] Gheorghiade M, Abraham WT, Albert NM, et al. Systolic
blood pressure at admission, clinical characteristics, and out-
comes in patients hospitalized with acute heart failure. JAMA
2006;296:2217—26.
[59] Berry C, Hogg K, Norrie J, Stevenson K, Brett M, McMurray J.
Heart failure with preserved left ventricular systolic function:
a hospital cohort study. Heart 2005;91:907—13.
[60] Grigorian Shamagian L, Gonzalez-Juanatey JR, Roman AV,
Acuna JM, Lamela AV. The death rate among hospitalized heart
failure patients with normal and depressed left ventricular
ejection fraction in the year following discharge: evolution
over a 10-year period. Eur Heart J 2005;26:2251—8.
[61] Gottdiener JS, McClelland RL, Marshall R, et al. Outcome of
congestive heart failure in elderly persons: influence of left
ventricular systolic function. The Cardiovascular Health Study.
Ann Intern Med 2002;137:631—9.
[62] Komajda M, Follath F, Swedberg K, et al. The EuroHeart Fail-
ure Survey programme–a survey on the quality of care among
patients with heart failure in Europe. Part 2: treatment. Eur
Heart J 2003;24:464—74.
[63] Lenzen MJ, Scholte op Reimer WJ, Boersma E, et al. Differences
between patients with a preserved and a depressed left ven-
tricular function: a report from the EuroHeart Failure Survey.
Eur Heart J 2004;25:1214—20.
[64] Bursi F, Weston SA, Redfield MM, et al. Systolic and diastolic
heart failure in the community. JAMA 2006;296:2209—16.
[65] Ahmed A, Roseman JM, Duxbury AS, Allman RM, DeLong JF.
Correlates and outcomes of preserved left ventricular systolic
function among older adults hospitalized with heart failure.
Am Heart J 2002;144:365—72.
[66] Dobre D, van Veldhuisen DJ, DeJongste MJ, et al. Prescription of
beta-blockers in patients with advanced heart failure and pre-
served left ventricular ejection fraction. Clinical implications
and survival. Eur J Heart Fail 2007;9:280—6.
[67] Aronow WS, Ahn C, Kronzon I. Effect of propranolol versus
no propranolol on total mortality plus nonfatal myocardial
infarction in older patients with prior myocardial infarc-
tion, congestive heart failure, and left ventricular ejection
fraction > or = 40% treated with diuretics plus angiotensin-
converting enzyme inhibitors. Am J Cardiol 1997;80:
207—9.
[68] Borghi C, Ambrosioni E. Effects of zofenopril on myocardial
ischemia in post-myocardial infarction patients with preserved
left ventricular function: the Survival of Myocardial Infarc-
tion Long-term Evaluation (SMILE)-ISCHEMIA study. Am Heart
J 2007;153(445):e7—14.
[69] Bertrand ME, Remme WJ, Fox KM, Ferrari R, Simoons ML.
Effects of perindopril on long-term clinical outcome of patients
with coronary artery disease and preserved left ventricular
function. Int J Cardiol 2007;121:57—61.
[70] Ahmed A, Rich MW, Fleg JL, et al. Effects of digoxin
on morbidity and mortality in diastolic heart failure:
the ancillary digitalis investigation group trial. Circulation
2006;114:397—403.
[71] Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of can-
desartan in patients with chronic heart failure and preserved
left-ventricular ejection fraction: the CHARM-Preserved Trial.
Lancet 2003;362:777—81.
[72] Flather MD, Shibata MC, Coats AJ, et al. Randomized trial to
determine the effect of nebivolol on mortality and cardiovas-
cular hospital admission in elderly patients with heart failure
(SENIORS). Eur Heart J 2005;26:215—25.
372
[73] Cleland JG, Tendera M, Adamus J, Freemantle N, Polon-
ski L, Taylor J. The perindopril in elderly people with
chronic heart failure (PEP-CHF) study. Eur Heart J 2006;27:
2338—45.
[74] Carson P, Massie BM, McKelvie R, et al. The irbe-
sartan in heart failure with preserved systolic function
(I-PRESERVE) trial: rationale and design. J Card Fail 2005;11:
576—85.
[75] Tresch DD. The clinical diagnosis of heart failure in older
patients. J Am Geriatr Soc 1997;45:1128—33.
[76] The SAGE Study GroupGambassi G, Forman DE, Lapane KL, et
al. Management of heart failure among very old persons living
in long-term care: has the voice of trials spread? Am Heart J
2000;139:85—93.
[77] Komajda M, Hanon O, Hochadel M, et al. Management of octo-
genarians hospitalized for heart failure in Euro Heart Failure
Survey I. Eur Heart J 2006;28:1310—8.
P. de Groote et al.
[78] Komajda M, Forette F, Aupetit JF, et al. Recommendations for
the diagnosis and management of cardic failure in the elderly
subject. Arch Mal Coeur Vaiss 2004;97:803—22.
[79] Galbreath AD, Krasuski RA, Smith B, et al. Long-term health-
care and cost outcomes of disease management in a large,
randomized, community-based population with heart failure.
Circulation 2004;110:3518—26.
[80] Gary RA, Sueta CA, Dougherty M, et al. Home-based exercise
improves functional performance and quality of life in women
with diastolic heart failure. Heart Lung 2004;33:210—8.
[81] Dubourg O, Gueret P, Beauchet A, Nisse-Durgeat S, Ducardon-
net A. Focale: Study of systolic and diastolic heart failure in a
French elderly population. Int J Cardiol 2007;124:188—92.
[82] Smith GL, Masoudi FA, Vaccarino V, Radford MJ, Krumholz HM.
Outcomes in heart failure patients with preserved ejection
fraction: mortality, readmission, and functional decline. J Am
Coll Cardiol 2003;41:1510—8.