Do Diuretics and Aldosterone Receptor
Antagonists Improve Ventricular Remodeling?
BERTRAM PITT, MD
Ann Arbor, Michigan
ABSTRACT
There is no evidence that loop diuretics improve ventricular remodeling in patients with heart
failure. Aldosterone receptor antagonists, which have an effect on natriuresis and diuresis,
especially in conjunction with an angiotensin converting enzyme–inhibitor, have been shown
to improve ventricular remodeling in patients with left ventricular systolic dysfunction. The
mechanisms for this beneficial effect and a reduction in death due to progressive heart failure
seen in the randomized aldosterone evaluation study (RALES) is likely related to the effect
of aldosterone receptor antagonism on myocardial collagen formation and ventricular
hypertrophy. Further proof of this hypothesis should be forthcoming from the results of the
Eplerenone Heart Failure Efficacy and Survival Study (EPHESUS) early in 2003 in which the
aldosterone receptor antagonist eplerenone is being evaluated in patients with systolic left
ventricular dysfunction post myocardial infarction.
Key Words: Left ventricular remodeling, diuretics, aldosterone receptor antagonist, myocardial
fibrosis, heart failure, myocardial infarction.
There is no evidence that diuretics improve ventricular
remodeling in patients with heart failure resulting from
systolic left ventricular dysfunction or those with an acute
myocardial infarction and systolic left ventricular dysfunction.
Sharp and colleagues have clearly demonstrated
that the loop diuretic furosemide failed to significantly
improve left ventricular remodeling in patients with an
acute myocardial infarction and systolic left ventricular
dysfunction in comparison to placebo.1 Patients randomized
to the angiotensin-converting enzyme (ACE) inhibitor
captopril in the same study were found to have a significant
improvement in left ventricular remodeling, as
assessed by echocardiography with a 1-year follow-up.
There is, however, increasing evidence to suggest that aldosterone
receptor antagonists are effective in preventing
ventricular remodeling both in patients with chronic heart
failure and those with acute myocardial infarction.
The Randomized Aldactone Evaluation Study
(RALES) showed that patients with severe heart failure
(New York Heart Association class IV within the past 6
months before randomization) treated with standard
therapy including an ACE inhibitor, loop diuretic,
digoxin, and/or a -adrenergic receptor blocking agent
who were randomized to the aldosterone receptor antagonist
spironolactone had a 30% improvement in
all-cause mortality in comparison to placebo (P < .001).2
This reduction in mortality was the result of both a
reduction in death from progressive heart failure and
sudden cardiac death. There was also a significant 35%
reduction in hospitalization for heart failure.
Spironolactone by blocking the aldosterone receptor
promotes natriuresis and retains potassium. Recent experimental
studies suggest that the combination of an
aldosterone receptor antagonists and an ACE inhibitor is
more effective in causing natriuresis than either is alone.3
It is, however, unlikely that the significant reduction in
mortality and morbidity seen with spironolactone in the
RALES trial can be attributed to a natriuretic effect. First,
as mentioned previously, loop diuretics do not affect left
ventricular remodeling,1 which is known to be an important
predictor of survival in patients with heart failure
From the University of Michigan School of Medicine, Ann Arbor
Michigan
Reprint requests: Bertram Pitt, MD, 1500 E. Medical Center Drive,
3910 Taubman Center, Ann Arbor, MI 48109-0366
Copyright 2002, Elsevier Science (USA). All rights reserved.
1071-9164/02/0806-0049$35.00/0
doi:10.1054/jcaf.2002.130014
Journal of Cardiac Failure Vol. 8 No. 6 Suppl. 2002
S491
resulting from systolic left ventricular dysfunction. Second,
patients in the RALES trial were on a loop diuretic,
and investigators were free to vary the dose of the loop
diuretic in both the placebo and spironolactone arms.2
Third, there was no significant improvement in the
sodium retention score, a clinical composite score reflecting
volume overload,4 between patients randomized
to spironolactone or placebo. Patients in New York Heart
Association Class IV had a significant increase in their
sodium retention score in comparison to those in class III
independent of randomization to placebo or spironolactone.
Although there was no direct measurement of left
ventricular remodeling in RALES it is likely that an
improvement in ventricular remodeling occurred and
was to a large degree responsible for or associated with
the improvement in survival.
Indirect evidence for an improvement in left ventricular
remodeling in RALES comes from a substudy of collagen
formation by Zannad and colleagues.5 In this study
it was found that patients with an elevation of procollagen
I and III, markers of ongoing collagen formation,
had a significant increase in mortality. Elevation of
pro-collagen I and III were strong independent markers
of mortality. Patients randomized to spironolactone had a
significant reduction in both pro-collagen I and III in comparison
to patients randomized to placebo. In patients with
an elevation of pro-collagen III at baseline spironolactone
significantly reduced pro-collagen III levels and increased
survival whereas, in those without an elevation of procollagen
III, spironolactone did not significantly reduce
pro-collagen III or mortality.
Spironolactone has been shown to prevent experimental
myocardial and perivascular fibrosis induced by
aldosterone.6,7 MacFayden and colleagues have shown
that spironolactone decreases collagen formation in patients
with mild to moderate heart failure, as reflected by
a decrease in pro-collagen III.8 Tsutamoto has demonstrated
an improvement in left ventricular volume and
ejection fraction in patients with chronic heart failure
treated with spironolactone.9 Myocardial fibrosis is
strongly correlated with left ventricular diastolic function.
10 It is therefore not surprising that spironolactone
has been shown to significantly improve left ventricular
diastolic function as reflected by a change in the echocardiographic
E/A ratio.11
Aldosterone has also been associated with an increase
in left ventricular mass. In patients with essential hypertension,
there is a significant correlation between serum
aldosterone levels and left ventricular mass.12 Conversely,
aldosterone receptor antagonism with spironolactone
has been shown to significantly reduce left
ventricular mass in patients with hypertension.13
The mechanisms associated with the effect of aldosterone
on myocardial fibrosis and hypertrophy are not
entirely clear. However, there are data to suggest that
aldosterone administration is associated with an increase
in transforming growth factor- (TGF- ) and renal
fibrosis.14 Aldosterone has been suggested to cause
microvascular inflammation and damage through activation
of osteopontin and other signaling molecules.15 This
microvascular inflammation and damage is thought to
result in myocardial and perivascular fibrosis. Recently
aldosterone has been suggested to be a hydroxyl radical
generator.16 In the stroke-prone hypertensive rat treated
with 1% sodium chloride and the ACE inhibitor lisinopril,
aldosterone causes significant renal tubular damage
and fibrosis. In this model dimethylthiourea, a hydroxyl
radical inhibitor, significantly reduces renal protein excretion
and fibrosis at a dose that has no significant effect
on systemic blood pressure. Aldosterone has also been
known to stimulate the NF- and activator protein-1
(AP-1) signaling pathways,17 which are known to be
associated with activation of various adhesion molecules
such as MCP-1, ICAM, and VCAM. It can therefore be
postulated that aldosterone, by stimulating the production
of oxygen-free radicals and the NF- and AP-1
signaling pathways, can cause microvascular inflammation,
vascular damage, and subsequent myocardial fibrosis.
The effects of aldosterone on left ventricular hypertrophy
appear to be independent of its effects on
myocardial fibrosis and may be related to an effect on
intracellular calcium concentration.18
In view of the beneficial effects of the aldosterone
receptor antagonist spironolactone on mortality and morbidity
in patients with severe heart failure resulting from
systolic left ventricular dysfunction, the Eplerenone
Heart Failure Efficacy and Survival Study (Ephesus) has
been undertaken to examine the effects of the specific
aldosterone receptor antagonist eplerenone in patients
with acute myocardial infarction and systolic left ventricular
dysfunction.19 Eplerenone appears to have
mineralocorticoid-blocking properties similar to that of
spironolactone but more specifically to block the aldosterone
receptor with less binding to androgen and prostagen
receptors,20 therefore potentially reducing the
incidence of gynecomastia, breast pain, menstrual irregularities,
and libido changes associated with spironolactone.
The Ephesus trial will randomize 6,200 patients
with acute myocardial infarction between day 3 and 14
after myocardial infarction to eplerenone or placebo.
Patients can be treated with standard therapy including
thrombolysis, direct percutaneous transluminal coronary
angioplasty (PTCA), ACE inhibitors, -receptor blocking
agents, aspirin, and a statin. The endpoints of this trial are
all-cause mortality and the combination of cardiovascular
mortality and hospitalization. The trial is endpoint-driven
and will continue until 1,012 deaths. The results are
expected in 2003. It is postulated that the aldosterone
receptor antagonist eplerenone will prevent ventricular
remodeling, reduce death resulting from progressive
S492 Journal of Cardiac Failure Vol. 8 No. 6 Suppl. 2002
heart failure and sudden cardiac death, reduce reocclusion
and reinfarction, and improve endothelial function
and progression of atherosclerosis. Initial support for this
hypothesis can be seen in a small randomized study of the
aldosterone receptor antagonist canrenoate that resulted
in a significant reduction in ventricular volume and
collagen formation after myocardial infarction.21
Although some of the mechanisms associated with the
beneficial effects of aldosterone antagonism have been
elucidated, our understanding remains incomplete. The
challenge to basic science is to further elucidate the
mechanisms by which aldosterone receptor antagonists
prevent ventricular remodeling and ventricular hypertrophy.
The challenge to clinical investigation is to extend
the benefits demonstrated with aldosterone receptor antagonists
in the RALES trial to a wider variety of
cardiovascular diseases, including patients with mild to
moderate heart failure resulting from systolic left ventricular
dysfunction, diastolic heart failure, essential
hypertension, and systolic hypertension.
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Ventricular remodeling O Bertram Pitt S493
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