Aldosterone receptor antagonists and cardiovascular disease: do we

need a change of the guard?

Jewell CW1, Watson LE, Mock J, Dostal DE.
Author information

Abstract
Aldosterone is a mineralocorticoid primarily produced in the zona glomerulosa of the adrenal gland. For
many years, aldosterone (Aldo) was thought to have its sole site of action in the kidney, where it regulated
sodium excretion and potassium reabsorption. It is now known that Aldo is produced in cardiovascular
tissues, and has been implicated in the development of ventricular hypertrophy and cardiac fibrosis. The
precise mechanisms whereby Aldo acts in cardiac tissues are diverse. It was assumed that Aldo
production could be limited by angiotensin-converting enzyme (ACE) inhibition, but serial measurements
during therapy reveal only a transient decrease in Aldo levels. Moreover, the effects of Aldo on cardiac
tissues occur even when angiotensin II (Ang II) has been suppressed or eliminated. Multiple investigators
have examined effects of Aldo receptor blockade in human subjects and various animal models using the
two Aldo receptor antagonists (ARAs), spironolactone and eplerenone. Major clinical trials involving
spironolactone (RALES) and eplerenone (EPHESUS) ARAs have shown significant benefits in the
treatment of congestive heart failure (CHF). In RALES, patients with New York Heart Association (NYHA)
Class III or IV systolic heart failure treated with spironolactone had a 30% relative risk decrease in
mortality. Although spironolactone is an effective competitive inhibitor of the mineralocorticoid receptor
(MR), progestational and antiandrogenic side effects limit its use in some patients. Eplerenone, a more
selective ARA, lacks these undesirable side effects. Although eplerenone is 20-fold less potent at the MR,
it demonstrates efficacy similar to spironolactone, possibly due to decreased protein binding. Eplerenone
has fewer side effects than spironolactone, which has been attributed to the low cross-reactivity with
androgen and progesterone receptors. In EPHESUS, patients with left ventricular systolic dysfunction
[Ejection Fraction (EF) <40%] and CHF following an acute myocardial infarction (AMI), were treated with
eplerenone, resulting in a 17% reduction in cardiovascular mortality. However, these studies were limited
in that diastolic function was not evaluated, although approximately 1/2 of CHF is due to diastolic
dysfunction alone. To date, neither ARA has been studied for the treatment of diastolic dysfunction in a
major clinical trial. However, numerous animal studies employing ARAs have shown a decrease in cardiac
hypertrophy and fibrosis, indicating the potential benefits of these agents in the treatment of diastolic
heart failure. In this review, we discuss possible underlying mechanisms responsible for Aldo effects on
cardiovascular function and compare the beneficial effects of spironolactone and eplerenone in the
treatment of heart disease.

Spironolactone in the treatment of congestive heart failure.

Lloyd SJ1, Mauro VF.

Author information

Abstract
OBJECTIVE:
To evaluate evidence supporting the use of spironolactone in managing congestive heart failure.
DATA SOURCES:
Literature accessed through MEDLINE (January 1966-December 1999) and cross-referencing of selected
articles. Search terms included spironolactone and heart failure.
DATA SYNTHESIS:
Heart failure is a leading cause of morbidity and mortality. Through aldosterone
antagonism, spironolactone may be an effective pharmacotherapeutic addition to patients not responding
to standard drug therapy for heart failure.
RESULTS:
Clinical trials have demonstrated that, in patients with heart failure, spironolactone improves laboratory
indices, quality of life, and morbidity. Recently, spironolactone has been demonstrated to improve the
survival of patients with New York Heart Association (NYHA) III or IV heart failure.
CONCLUSIONS:
Spironolactone use should be considered in patients with NYHA Class III or IV heart failure.
PMID:

11098350

[PubMed - indexed for MEDLINE]

[The role of aldosterone-antagonists in the treatment of congestive

heart failure].

[Article in Hungarian]

Fgedi K1.
Author information

Abstract
The role of aldosterone-antagonists in the treatment of congestive heart failure. Despite the advances of
the treatment of congestive heart failure, nearly half of the patients diagnosed with this disease five years
ago are alive today. Experimental and human studies have demonstrated, that under special pathologic
condition, the heart extracts aldosterone, and aldosterone extraction in the heart stimulates increased
collagen turnover culminating in ventricular remodeling. Aldosterone blockade has been shown to be
effective in reducing total mortality and hospitalization for heart failure in patients with systolic left
ventricular dysfunction due to chronic heart failure (RALES study with spironolactone) and in patients with
systolic left ventricular dysfunction post acute myocardial infarction (EPHESUS study with eplerenone).
These clinical studies have shown that mineralocorticoid receptor activation remains important despite the
use of angiotensin converting enzyme inhibitor or angiotensin receptor blocking agent and a beta blocker.
In the ACC/AHA (and in the European and Hungarian) guidelines for the evolution and management of
chronic heart failure, the indication of spironolactone was defined of Class Ila, Level of Evidence: B in
CHF of stage C. The eplerenone (in US: INSPRA) was approved for the management of CHF patients
after myocardial infarction with ejection fraction < 40%. Eplerenone, compared with spironolactone, is
associated with a lower incidence of gynecomastia and other sex hormone-related adverse effect (breast
pain, menstrual abnormalities). The spironolactoneshould not be used in patients with a creatinine above
220 mikromol/l. Despite the guidelines recommendation, spironolactone has been widely used in patients
without consideration of their functional class or ejection fraction, without optimization of background
treatment with ACE inhibitors and beta-blockers.
2005 Nov-Dec;31(6):97-105.

Cardioprotection by aldosterone receptor antagonism in heart failure.

Part I. The role of aldosterone in heart failure.
Dieterich HA1, Wendt C, Saborowski F.
Author information

Abstract
In recent years understanding of the role of aldosterone has expanded beyond the known classic effects
of promoting renal sodium retention and potassium and magnesium loss. It is now well documented that
aldosterone causes myocardial and perivascular fibrosis, blocks the myocardial uptake of norepinephrine,
and increases plasminogen activator inhibitor levels. In conjunction with angiotensin II, aldosterone
causes vascular damage, endothelial dysfunction, and decreased vascular compliance. Therefore, the
renin-angiotensin-aldosterone system (RAAS) plays a major role in the development of both hypertension
and heart failure and is therefore, a key target for therapeutic interventions. Commonly prescribed

medications for control of hypertension and congestive heart failure are inhibitors of the RAAS, including
angiotensin converting enzyme inhibitors (ACE-I) and Angiotensin II (A-II) receptor antagonists. There is a
well-documented increase in aldosterone levels that occurs over several months during chronic treatment
with an ACE-I or A-II receptor antagonist. Such suppression of circulating aldosterone however, is
transient, as exemplified by the term "escape" used to describe the phenomenon. This rebound of
aldosterone even occurs when patients receive both an ACE-I and A-II receptor antagonist. In addition,
ACE-I and A-II receptor antagonists are less effective in controlling BP in the estimated 60% of
hypertensive patients who are salt (volume) sensitive and more prone to hypertension-associated
morbidity such as black patients and type 2 diabetics. Thus chronic and complete blockade of aldosterone
action requires an aldosterone receptor antagonist. The "Randomized Aldactone Evaluation Study"
(RALES) trial results in patients with severe heart failure NYHA class III or IV and a left ventricular
ejection fraction of no more than 35 percent showed that administration of a sub-hemodynamic dose
of spironolactone (25 mg a day) as an add on therapy to ACE-I plus standard treatment resulted in a
significant mortality reduction due both to decreased death from progressive heart failure and sudden
cardiac death. These findings support the pivotal role of aldosterone in the pathophysiology of
progressive heart failure. Although it is an effective antialdosterone agent, widespread use
of spironolactone in humans is limited by its tendency to produce undesirable sexual side effects. At
standard doses, impotence and gynaecomastia can be induced in men, whereas pre-menopausal women
may experience menstrual disturbances. Data on a selective aldosterone receptor antagonist,
eplerenone, appear promising for the effective blockade of aldosterone and its harmful effects without the
sexual disturbances ofspironolactone. Recently Eplerenone was successfully introduced for the treatment
of hypertension and heart failure. Growing number of experimental studies are finding a broader role for
Aldosterone in driving the pathophysiology of both heart failure and hypertension. When added to
conventional therapy aldosterone receptor blockers show benefits which are in addition to those conferred
by ACE-I and/or AII receptor blockers.

2007 Dec;4(4):183-9.

Optimizing care of heart failure after acute MI with an aldosterone

receptor antagonist.
Verma A1, Solomon SD.
Author information

Abstract
The presence of heart failure or left ventricular systolic dysfunction in the setting of acute myocardial
infarction is associated with poor prognosis. Aldosterone is an important downstream mediator of the
renin-angiotensin-aldosterone system that promotes myocardial collagen deposition, myocardial fibrosis,
apoptosis, ventricular remodeling, and endothelial dysfunction. It may play an important role in the

increased morbidity and mortality and the development and progression of heart failure after acute
myocardial infarction. Extending the findings from the Randomized Aldactone Evaluation Study (RALES)
in patients with chronic heart failure, the Eplerenone Post-Acute Myocardial Infarction Heart Failure
Efficacy and Survival Study (EPHESUS) demonstrated that the selective aldosterone blocker eplerenone
offered a significant survival benefit, attenuation of progression of heart failure, and prevention of sudden
cardiac death when used in addition to optimal medical therapy. The current evidence-based guidelines
now suggest that aldosterone blockade should be an integral component of heart failure therapy to
improve outcomes in this high-risk population.
PMID:

18221614

[PubMed - indexed for MEDLINE]

2003 Apr;51(2):155-64.

Aldosterone antagonism in addition to angiotensin-converting enzyme

inhibitors in heart failure.
Bauersachs J1, Fraccarollo D.
Author information

Abstract
Although the role of the systemic renin-angiotensin-aldosterone system in the pathophysiology of heart
failure is well-known for years, the impact of a local cardiac aldosterone system has been recognized
recently. Aldosterone promotes cardiac hypertrophy and fibrosis in hypertension and heart failure and is
involved in left ventricular remodeling after myocardial infarction. Plasma aldosterone levels in patients
with heart failure are an indicator of a worse prognosis. Although ACE inhibitor therapy in these patients
reduces plasma aldosterone levels, this effect is only transitory, a phenomenon referred to as
"aldosterone escape". Even maximally recommended doses of ACE inhibitors do not completely prevent
ACE-mediated formation of angiotensin II in chronic heart failure, and those patients with increased
aldosterone levels during ACE inhibition have impaired exercise capacity. The RALES study has
demonstrated convincingly that in patients with heart failure, addition of the mineralocorticoid receptor
antagonist spironolactone (25 mg/d) to ACE inhibition markedly reduces mortality and prevents worsening
heart failure. While reduction of excessive extracellular matrix turnover leading to decreased fibrosis
appears to be the most important effect of spironolactone in heart failure, other mechanisms such as
regression of hypertrophy, improvement of endothelial function, enhanced renal sodium excretion and
antiarrhythmic actions may contribute. In RALES, low-dose spironolactone did not confer a substantial

risk of hyperkalemia, however, with broader use of spironolactone in heart failure, cases of hyperkalemia
associated with the use of this drug increase. Close control of serum potassium and creatinine and
estimation of creatinine clearance are mandatory, especially in the presence of additional factors
impairing renal function. The new and more selective aldosterone antagonist eplerenone which is devoid
of some side effects of spironolactone, has been shown to be effective in hypertension and holds great
promise as future therapeutic agent in patients with heart failure.

2006 Jun;24(6):983-91.

Role of the renin-angiotensin-aldosterone system in vascular

remodeling and inflammation: a clinical review.
Duprez DA1.
Author information

Abstract
The concept of hypertension as primarily a consequence of altered hemodynamics has changed. Many
factors are now implicated in the development of hypertensive vascular disease, and the reninangiotensin-aldosterone system (RAAS) appears to be one of the most significant. Angiotensin II, the
principal effector peptide of the RAAS, has far-reaching effects on vascular structure, growth and fibrosis,
and is a key regulator of vascular remodeling and inflammation. Reactive oxygen species and a network
of signaling pathways mediate angiotensin II and cellular mechanisms that promote remodeling and
inflammation. The involvement of aldosterone in vessel-wall and myocardial remodeling has also come
under intensive research scrutiny. Treatments that block the pathologic effects of the RAAS at several
points have been shown to limit target-organ damage in hypertension and to decrease cardiovascular
morbidity and mortality. Understanding the molecular and cellular mechanisms that participate in the early
development of hypertensive vascular disease may lead to more targeted treatment and improved
outcomes.

1995 Dec;16 Suppl N:107-10.

ACE inhibitor co-therapy in patients with heart failure: rationale for the
Randomized Aldactone Evaluation Study (RALES).
Pitt D1.

Author information

Abstract
Angiotensin converting enzyme (ACE) inhibitor therapy in conjunction with loop diuretics and, possibly,
digoxin, is associated with a relatively high incidence of recurrent heart failure and death. Even high
doses of ACE inhibitors may not completely suppress the renin-angiotensin-aldosterone system;
aldosterone "escape' may occur through non-angiotensin II dependent mechanisms involving
corticotropin, atrial natriuretic peptide, serum potassium, and deficient high-density lipoprotein cholesterol
concentrations. Addition of spironolactone (an aldosterone receptor blocker) to an ACE inhibitor regimen
causes marked diuresis and symptomatic improvement. The Randomized Aldactone Evaluation Study
(RALES) was organized to explore the role of combination therapy with spironolactone in patients with
heart failure. Patients with New York Heart Association Functional Class II-IV heart failure and left
ventricular ejection fractions < or = 40% who were on regimens comprising an ACE inhibitor, loop diuretic,
and, possibly, digoxin were randomized to receive placebo or spironolactone in doses of 12.5, 25, 50, or
75 mg per day. Eve at the lowest dose of spironolactone, a significant decrease in plasma N-terminal proatrial natriuretic peptide occurred, with concomitant increase in concentrations of plasma renin and
urinary aldosterone. As prophylaxis for heart failure, a daily dose of 25 mg of spironolactone and
monitoring of serum potassium concentrations are recommended; symptomatic therapy in refractory or
severe heart failure may require doses as high as 100 mg b.i.d. The RALES Mortality Trial willfollow up
1400 similar patients for 3 years to determine the effect of the addition of spironolactone on combined
mortality and hospitalization for heart failure.

2003 Apr;51(2):155-64.

Aldosterone antagonism in addition to angiotensin-converting enzyme

inhibitors in heart failure.
Bauersachs J1, Fraccarollo D.
Author information

Abstract
Although the role of the systemic renin-angiotensin-aldosterone system in the pathophysiology of heart
failure is well-known for years, the impact of a local cardiac aldosterone system has been recognized
recently. Aldosterone promotes cardiac hypertrophy and fibrosis in hypertension and heart failure and is
involved in left ventricular remodeling after myocardial infarction. Plasma aldosterone levels in patients
with heart failure are an indicator of a worse prognosis. Although ACE inhibitor therapy in these patients
reduces plasma aldosterone levels, this effect is only transitory, a phenomenon referred to as
"aldosterone escape". Even maximally recommended doses of ACE inhibitors do not completely prevent
ACE-mediated formation of angiotensin II in chronic heart failure, and those patients with increased

aldosterone levels during ACE inhibition have impaired exercise capacity. The RALES study has
demonstrated convincingly that in patients with heart failure, addition of the mineralocorticoid receptor
antagonist spironolactone (25 mg/d) to ACE inhibition markedly reduces mortality and prevents worsening
heart failure. While reduction of excessive extracellular matrix turnover leading to decreased fibrosis
appears to be the most important effect of spironolactone in heart failure, other mechanisms such as
regression of hypertrophy, improvement of endothelial function, enhanced renal sodium excretion and
antiarrhythmic actions may contribute. In RALES, low-dose spironolactone did not confer a substantial
risk of hyperkalemia, however, with broader use of spironolactone in heart failure, cases of hyperkalemia
associated with the use of this drug increase. Close control of serum potassium and creatinine and
estimation of creatinine clearance are mandatory, especially in the presence of additional factors
impairing renal function. The new and more selective aldosterone antagonist eplerenone which is devoid
of some side effects of spironolactone, has been shown to be effective in hypertension and holds great
promise as future therapeutic agent in patients with heart failure.

Cardioprotection by aldosterone receptor antagonism in heart failure.

Part I. The role of aldosterone in heart failure.
Dieterich HA1, Wendt C, Saborowski F.
Author information

Abstract
In recent years understanding of the role of aldosterone has expanded beyond the known classic effects
of promoting renal sodium retention and potassium and magnesium loss. It is now well documented that
aldosterone causes myocardial and perivascular fibrosis, blocks the myocardial uptake of norepinephrine,
and increases plasminogen activator inhibitor levels. In conjunction with angiotensin II, aldosterone
causes vascular damage, endothelial dysfunction, and decreased vascular compliance. Therefore, the
renin-angiotensin-aldosterone system (RAAS) plays a major role in the development of both hypertension
and heart failure and is therefore, a key target for therapeutic interventions. Commonly prescribed
medications for control of hypertension and congestive heart failure are inhibitors of the RAAS, including
angiotensin converting enzyme inhibitors (ACE-I) and Angiotensin II (A-II) receptor antagonists. There is a
well-documented increase in aldosterone levels that occurs over several months during chronic treatment
with an ACE-I or A-II receptor antagonist. Such suppression of circulating aldosterone however, is
transient, as exemplified by the term "escape" used to describe the phenomenon. This rebound of
aldosterone even occurs when patients receive both an ACE-I and A-II receptor antagonist. In addition,
ACE-I and A-II receptor antagonists are less effective in controlling BP in the estimated 60% of
hypertensive patients who are salt (volume) sensitive and more prone to hypertension-associated
morbidity such as black patients and type 2 diabetics. Thus chronic and complete blockade of aldosterone
action requires an aldosterone receptor antagonist. The "Randomized Aldactone Evaluation Study"
(RALES) trial results in patients with severe heart failure NYHA class III or IV and a left ventricular
ejection fraction of no more than 35 percent showed that administration of a sub-hemodynamic dose
of spironolactone (25 mg a day) as an add on therapy to ACE-I plus standard treatment resulted in a
significant mortality reduction due both to decreased death from progressive heart failure and sudden

cardiac death. These findings support the pivotal role of aldosterone in the pathophysiology of
progressive heart failure. Although it is an effective antialdosterone agent, widespread use
of spironolactone in humans is limited by its tendency to produce undesirable sexual side effects. At
standard doses, impotence and gynaecomastia can be induced in men, whereas pre-menopausal women
may experience menstrual disturbances. Data on a selective aldosterone receptor antagonist,
eplerenone, appear promising for the effective blockade of aldosterone and its harmful effects without the
sexual disturbances ofspironolactone. Recently Eplerenone was successfully introduced for the treatment
of hypertension and heart failure. Growing number of experimental studies are finding a broader role for
Aldosterone in driving the pathophysiology of both heart failure and hypertension. When added to
conventional therapy aldosterone receptor blockers show benefits which are in addition to those conferred
by ACE-I and/or AII receptor blockers.