Editorial
Hypertension, Heart Failure, and Ejection Fraction
William C. Little, MD
M ore than three quarters of patients with heart failure
(HF) have antecedent hypertension.1 Hypertension ap-
pears to play an especially important role in HF associated
with a preserved ejection fraction (EF) ⬎0.50 (HFPEF). No
proven specific therapy exists for HFPEF, but treatment of
systolic hypertension in the elderly (the group at greatest risk
for developing HFPEF) reduces the risk of developing HF by
about one half.2,3 The current issue of Circulation contains an
important analysis of the Antihypertensive and Lipid-
Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
on the effect of the initial drug used to treat hypertension on
the subsequent risk of HF requiring hospitalization stratified
Downloaded from http://circ.ahajournals.org/ by guest on July 18, 2017
by EF.4
Article p 2259
ALLHAT studied ⬎42 000 hypertensive patients over 55
years of age with at least 1 other coronary artery disease risk
factor.5 The patients were randomized to receive the initial
treatment of their hypertension with a calcium channel
blocker (amlodipine), an angiotensin-converting enzyme
(ACE) inhibitor (lisinopril), an ␣-adrenergic blocker (doxazo-
sin), or a thiazide diuretic (chlorthalidone). As expected,
many of the patients (40% at 5 years) required the addition of
other medications to control their hypertension.
Davis et al4 identified in the ALLHAT patients 1367
hospitalizations classified as being for HF on the basis of a
review of the hospital records. Two thirds of these patients
had a determination of their EF. This study includes 3 key
findings. First, nearly one half of the patients had HFPEF. As
expected, these were frequently older women. Second, the
patients with HFPEF had a high mortality, but not as high as
those who subsequently developed HF with reduced EF
⬍0.50 (HFREF). The third and most important finding was
that initial treatment of hypertension with a thiazide diuretic
reduced the risk of HFPEF compared with the other therapies.
Among patients who subsequently developed HF with a
reduced EF, the thiazide and ACE inhibitor were equally
effective in reducing the risk of HF.
The EF was not measured at the time of entry into the
study. Because patients were enrolled only if they had no
history of HF or reduced EF, we can speculate that most had
a normal EF on entry. In treating a patient with hypertension
The opinions expressed in this article are not necessarily those of the
editors or of the American Heart Association.
From the Section of Cardiology, Wake Forest University School of
Medicine, Winston-Salem, NC.
Correspondence to William C. Little, MD, Cardiology Section, Wake
Forest University School of Medicine, Medical Center Blvd, Winston-
Salem, NC 27157–1045. E-mail wlittle@wfubmc.edu
(Circulation. 2008;118:2223-2224.)
© 2008 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org
DOI: 10.1161/CIRCULATIONAHA.108.819318
2223
who has a low EF, we can safely assume that if HF
subsequently develops, it will be associated with a reduced
EF. The finding that using an ACE inhibitor or a thiazide as
initial therapy was equally effective in patients who devel-
oped HF with a reduced EF is consistent with the previous
observations that using an ACE inhibitor in patients with an
EF ⬍0.35 reduces the risk of subsequently developing HF.6,7
Thus, an ACE inhibitor should be included in the initial
therapy in patients with hypertension and clearly reduced EF.
In the absence of knowledge of the EF or a normal EF, we
do not know if a patient with hypertension will subsequently
develop HFPEF or HFREF. In these patients, the initial use of
a thiazide would be reasonable. Adding an ACE inhibitor as
a second step, if needed, would be reasonable and is sup-
ported by the recent Hypertension in Very Elderly Trial
(HYVET).2
It is possible that the ALLHAT analysis overestimates the
frequency of HFREF in hypertensive patients by including
many men and patients as young as 55 years. We do not have
information on how many of the HFREF patients had
intervening myocardial infarctions that could be a reason why
the EF was reduced. It is important to note that the presence
of another coronary disease risk factor was an entry criterion
for the study, and about half of the patients had clinical
evidence of atherosclerotic cardiovascular disease.5 If an
older population with more women and without clinical
evidence of coronary disease were studied, it is likely that an
even higher portion of the HF would be HFPEF.
The analysis of the ALLHAT population was accom-
plished using the usual EF cut point of 0.50. Those above
0.50 were considered to have HFPEF and those below to have
HFREF. The use of 0.50 as the “lower limit” of normal is
convenient because it is an easily remembered round number.
However, the true lower limit of normal left ventricular EF is
higher. For example, when measured by magnetic resonance
imaging, the lower 5% confidence limit of normal is 0.59 in
men and 0.60 in women.8 Similarly, Lam et al9 found that the
EF assessed by echocardiography in a large sample (N ⫽617)
of healthy adults from the Olmstead County general popula-
tion was 0.63⫾0.05 (mean⫾SD). Thus, if EF ⬎0.50 is used
as the definition of HFPEF, it will include some patients
whose EF is lower than normal.
Putting a patient with an EF of 0.51 in one group (HFPEF)
and a patient with an EF of 0.49 in another group (HFPEF) is
making a distinction without a difference. This is especially
apparent when one considers the size of the potential error in
measuring EF. Furthermore, in the ALLHAT analysis, 201
patients only had a subjective evaluation of EF as normal,
borderline, or impaired.
The patients in ALLHAT did not neatly fall into 2 groups
divided at an EF of 0.50. Davis et al4 reported that 44% had
EF ⬎0.50, 21% had EF between 0.40 and 0.50, 17% between
 2224 Circulation November 25, 2008
0.30 and 0.40, and 21% with EF ⬍0.30. This pattern is
consistent with large American and European registries10,11
which demonstrate that patients hospitalized with HF have
the entire range of EFs, including normal, mildly reduced,
and severely reduced. Thus, HF should no longer be equated
with a low EF because HF can occur with any level of EF.
Unfortunately, in the past, the large randomized studies that
guide therapy of HF used an EF ⬍0.35 or 0.30 as an entry
criterion.12
Left ventricular EF has been used as the clinical gold
standard for systolic function, and patients with EF ⬎0.50
have been considered to have normal systolic function.
However, EF is not always a clear-cut measure of systolic
contractile function. For example, many patients with HFPEF
may have subtle abnormalities of systolic contractile func-
tion.13 Furthermore, the EF can be reduced in a patient with
normal systolic function by markedly elevated left ventricular
afterload.
The EF is calculated as stroke volume divided by end-di-
Downloaded from http://circ.ahajournals.org/ by guest on July 18, 2017
astolic volume. Thus, a reduced EF indicates that the end-di-
astolic volume is increased relative to the stroke volume. In
the absence of shock or marked tachycardia, most stable
patients with HF have near normal stroke volumes regardless
of EF.13 Thus, in such patients, the degree of reduction of EF
indicates the amount of left ventricular dilation. It is now
clear that patients may present with HF having no left
ventricular dilation (normal EF and end-diastolic volume) or
moderate or severe dilation (EF ⬍0.30, markedly increased
end-diastolic volume). It is possible that patients who present
with HF and no left ventricular dilation have a fundamentally
different disease than patients who do not develop clinically
apparent HF until after the left ventricle has dilated and the
EF has fallen.14 This concept is supported by the differing
effects of an ACE inhibitor in preventing the development of
HFPEF and HFREF.4
In conclusion, patients with antecedent hypertension may
be subsequently hospitalized with HF with the entire range of
left ventricular EFs. Treating hypertension is effective in
reducing the risk of developing HF. Initiating therapy with a
thiazide diuretic in patients with hypertension and a normal
EF is further supported by this important analysis of the
ALLHAT data by Davis et al.4
Acknowledgments
The author gratefully acknowledges the assistance of Amanda
Burnette in the preparation of this manuscript.
Disclosures
Dr Little is employed by Wake Forest University Health Sciences
and has been a consultant to the following: Bio-Control Medical,
Boston Scientific, Bristol-Myers Squibb, Celladon Corp, CorAssist
Cardiovascular Ltd, CVRx Inc, CV Therapeutics, and Medtronic Inc.
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KEY WORDS: Editorial 䡲 heart failure 䡲 hypertension 䡲 ejection fraction
 Hypertension, Heart Failure, and Ejection Fraction
William C. Little

Circulation. 2008;118:2223; originally published online November 10, 2008;

doi: 10.1161/CIRCULATIONAHA.108.819318
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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