1. health and fitness
2. disease

European Heart Journal Supplements (2002) 4 (Supplement G), G45–G50
How to best to counteract the enemies?
By blocking neurohormonal activation
J. Soler-Soler and D. García-Dorado
Servicio de Cardiología, Hospital Universitari Vall d’Hebron, Barcelona, Spain
regression of myocardial hypertrophy that is associated with
certain treatments. The results of clinical studies are not
consistent with a prominent role of apoptosis induced by
neurohormonal activation in the progression of heart failure.
Beta-blockers, inhibitors of the renin–angiotensin–aldosterone
system and angiotensin receptor antagonists improve
symptoms and prolong life, but are not able to prevent
progression of heart failure. The hypothesis that the beneficial
effect of blockade of neurohormonal activation in patients with
heart failure is, to a significant extent, due to reduced
cardiomyocyte apoptosis is still to be proven.
(Eur Heart J Supplements 2002; 4 (Suppl G): G45–G50)
© 2002 The European Society of Cardiology
Introduction
adaptive changes in the adrenergic system, the renin–
angiotensin–aldosterone system (RAAS) and several other
vasoactive hormones (Table 1) that are globally termed
‘neurohormonal activation’[1]. Although it has been well
demonstrated that interfering with some of these
neurohormones may improve symptoms and prolong
survival of patients with heart failure, progression of heart
failure continues to be a major challenge because there is no
evidence that the present therapeutic approach significantly
prevents this relentless progression.
Apoptosis probably plays an important role in the
progression of heart failure. Therefore, a brief review of the
role of neurohormonal activation blockers to prevent
cardiomyocyte death may be useful to treating physicians.
At the beginning of the 21th century, the principal
aetiopathogenic mechanisms of most myocardial diseases
are well established. The causative roles of ischaemia/
reperfusion, hypoxia, and injury by pathogenic microorganisms or by the immune system, chemotoxicity and
mechanical stress are well defined. Most cardiac diseases
are characterized by myocardial dysfunction, and in general
involve differing degrees of cardiomyocyte loss (cell death),
cardiomyocyte dysfunction (arrhythmias, contractile
failure), non-cardiomyocyte cell alterations (microvascular
and interstitial cells) and neurohormonal activation[1].
One of the most important clinical manifestation of
cardiac diseases is heart failure, a highly prevalent condition
that markedly reduces life expectancy and increases
morbidity[2], with an enormous and increasing socioeconomic impact. Heart failure is invariably associated with
Correspondence: Jordi Soler-Soler, MD, Servicio de Cardiología,
Hospital Universitari Vall d’Hebron, P. vall d’Hebron, 119–129,
08035 Barcelona, Spain.
1520-765X/02/0G0045 + 06 $35.00/0
Key Words: ACE inhibitors, apoptosis, beta-blockers, heart
failure, neurohormonal activation.
Contribution of cell death to
progressive ventricular dysfunction
Although not universal, there is wide agreement that
cardiomyocyte cell death in failing myocardium occurs
mainly through apoptosis[3,4]. Apoptotic cell death is the
© 2002 The European Society of Cardiology
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Progression of heart failure is associated with an increased rate
of cardiomyocyte apoptosis, and it has been hypothesized that
this may, to an important extent, be due to neurohormonal
activation. Experimental studies in cells and intact myocardium
show that mild prolonged ischaemia, cytokine activation, and
stimulation of G-protein-coupled receptors by adrenergic
agonists and angiotensin II may trigger apoptotic cardiomyocyte death. However, the complex intracellular signal
cascades that initiate apoptosis are not well understood but are
inextricably superimposed on those that trigger hypertrophy.
The net effect of neurohormonal activation on cardiomyocyte
apoptosis is highly dependent on experimental conditions. In
addition, recent studies support the existence of cardiomyocyte
regeneration, rendering even more complex the relationship
between increased apoptosis and net cell loss. In addition, other
studies suggest that apoptotic cell loss may contribute to the
G46
J. Soler-Soler and D. García-Dorado
Table 1 Chronic heart failure: neurohormones and cytokine activation
Norepinephrine
Epinephrine
Renin
Angiotensin II
Aldosterone
Arginine vasopressin
Neuropeptide Y
Vasopeptidases
Prostaglandins
Atrial natriuretic peptide
Endothelin
Beta-endorphins
Calcitonin
Growth hormone
Cortisol
TNF-alpha
Neurokinin A
Substance P
TNF=tumour necrosis factor.
Apoptosis in the failing myocardium
An increased rate of apoptosis has been convincingly
demonstrated in patients with heart failure secondary to
cardiomyopathy of various aetiologies[8]. Several mechanisms may account for the increase in rate of apoptotic cell
death: focal ischaemia, autoimmune injury and inflammation, and sustained adrenergic or RAAS stimulation
associated with neurohormonal activation.
Focal ischaemia in the failing heart may occur, among
other causes, as a consequence of inadequate microvascular
adaptation to hypertrophy, altered perfusion pressure
gradient or coronary microvascular disease. During
ischaemia, enhanced generation of radical oxygen species
(ROS), severe adenosine triphosphate depletion, increased
intracellular calcium and other alterations in cell
homeostasis are potent stimuli for initiation of apoptosis.
Although execution of the apoptotic cell death programme
requires energy, in vitro studies have shown that apoptosis
can occur under severe hypoxia, and thus during myocardial
ischaemia. It has been suggested that apoptosis may be a
particularly important form of death in cells exposed to
prolonged, mild ischaemia, as can occur in patients with
cardiomyopathy and heart failure. However, the importance
of apoptosis as a form of cardiomyocyte cell death during
ischaemia is unclear because of the increasingly apparent
limitations inherent to the methods used for its
quantification in reperfused myocardium[9]. Recently,
studies conducted in isolated cardiomyocytes and intact
hearts found that the susceptibility to develop apoptosis in
response to ROS or nitric oxide (NO) is increased in
Eur Heart J Supplements, Vol. 4 (Suppl G) November 2002
cardiomyocytes that are re-energized after prolonged
ischaemia[10,11]. This protection against apoptosis lasts for
the initial few hours of reperfusion, and its mechanism is
thus far unknown[12].
Cytokine activation as a consequence of various forms of
stress, including ischaemia and inflammation, may lead to
cardiomyocyte apoptosis. Myocardial and blood cells
(cardiomyocytes, endothelial cells, neutrophils and
platelets) may release multiple cytokines (tumour necrosis
factor [TNF]-alpha, interleukin-1, interleukin-6, platelet
activating factor and growth tissue factor). Cytokines act
through an intricate network of signalling systems to induce
multiple and important (and often opposed) cellular effects
such as hypertrophy, proliferation and apoptosis. Different
signalling pathways initiated by a cytokine may have
redundant, additive or opposing actions on a downstream
step of the signalling cascade, and these actions may be
dependent on the concentration of cytokines and time, and
may be modulated by signals from other network nodes.
The resulting complexity usually makes it impossible to
predict the effect of particular cytokines under different
conditions. For example, it is well known that TNF-alpha
may induce apoptosis[13], but on the other hand it upregulates nuclear factor-kappaB that has an antiapoptotic
effect[14], and the net effect depends on many conditions. In
fact, there is considerable overlap between the signalling
systems that are responsible for hypertrophy, proliferation
and apoptosis. Accordingly, the observation that in certain
conditions up-regulation of a pro-apoptotic cytokine is
associated with increased apoptotic rate does not allow one
to conclude that a cause–effect relationship exists between
them. A similar degree of complexity can be observed in the
signalling cascades induced by G-protein-coupled receptor
activation or by NO.
Role of neurohormonal activation
Prolonged exposure to abnormally high levels of
adrenergic agonists is a hallmark of neurohormonal
stimulation in patients with chronic heart failure[15]. In
previous studies conducted in isolated cardiomyocytes, it
was shown that sustained beta-1 adrenergic receptor (AR)
stimulation may cause apoptotic cell death via cyclic
adenosine
monophosphate-dependent
signalling,
involving the voltage-dependent calcium influx channel.
In fact, myocardial over-expression of beta-1 AR is
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result of the execution of a genetic programme that includes
activation of specific enzyme systems, among which
caspases play a major role, and eventually leads to internucleosomal DNA cleavage and fragmentation of the cell
(without sarcolemmal rupture) into vesicles that are
phagocytosed by other cells. In contrast to necrotic cell
death, apoptosis requires energy, does not result in the
release of intracellular contents (enzymes) and results in
much less inflammatory reaction. In addition to the its
important role in cardiac development during embryogenesis, there is solid evidence that cardiomyocyte apoptosis
occurs in many different contexts, including ischaemia/
reperfusion, hypertrophy and regression of hypertrophy,
cardiomyopathy, xenograft rejection and heart failure[5–7].
Blocking neurohormonal activation
From apoptosis to net cell loss
Evidence of cardiomyocyte apoptosis in failing
myocardium does not necessarily mean that an abnormal
reduction in the number of these cells is taking place.
Apoptosis is also consistently found in normal
myocardium, which indicates that either a progressive
reduction in the number of cardiomyocytes can be normal
or that cardiomyocyte regeneration can compensate for
apoptotic cell death. Despite occasional reports of
cardiomyocyte mitosis in adult myocardium, the
impossibility of adult, terminally differentiated
cardiomyocytes to undergo mitosis has been and is
considered a valid dogma for most scientists. However,
recent studies suggest the possibility of cardiomyocyte
regeneration from undifferentiated cells (stem cells,
cardiomyoblasts or bone marrow cells)[25,26]. Implantation
of cytokine mobilized bone marrow cells in infarcted mice
hearts, and ultimate differentiation into adult contracting
myocytes has recently been demonstrated [26]. The
presence of cardiomyocytes with the host genotype in
transplanted hearts demonstrates that cardiomyocyte
regeneration can occur spontaneously in patients[27].
Recent studies have described the coexistence of increased
apoptosis with normal ventricular function in the rat
heart[28]. Thus, at present, increased apoptotic rate cannot
be assumed to reflect increased cardiomyocyte cell loss
because it is not known whether and to what extent
increased cell death rate can be compensated for by
cardiomyocyte regeneration. Furthermore, a net cell loss
does not necessarily imply a relevant deterioration in
ventricular function. Finally, to make the issue even more
complex, it has been suggested that apoptosis may play an
important beneficial role in the regression of hypertrophy
secondary to hypertension[29].
Clinical benefit of blockers of
neurohormonal activation
There is clinical evidence to support the concept that
blocking some of the neurohormonal systems has a
significant benefit, with prolonged survival and improved
morbidity in patients with systolic left ventricular
dysfunction, and both patients with ischaemic and those
with non-ischaemic heart disease. In fact, at present, the
treatment of choice in such patients is blockade of both the
RAAS and the sympathetic nervous system. However, all
that glitters is not gold[30], because recent trials have
shown that blockade of some neurohormones, on top of
standard therapy, did not result in further reduction in
mortality. On the other hand, all of these important
beneficial effects are not translated into real prevention of
progression of heart failure, the prognosis of which
continues to be dismal. In the following paragraphs the
discussion focuses on clinical experience with several
neurohormonal blockers.
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associated with myocyte apoptosis and the development of
dilated cardiomyopathy. However, the pro-apoptotic effect
of beta-1 AR stimulation can be opposed by stimulation of
beta-2 AR, whereas stimulation of alpha-1 AR causes
myocyte hypertrophy and may exert an antiapoptotic
action as well[16,17]. The net balance between proapoptotic and antiapoptotic actions associated with
adrenergic up-regulation and desensitization of the betaadrenergic pathway in patients with heart failure is not
well established.
Angiotensin II was shown in vitro to be able to initiate
apoptosis in adult cardiomyocytes, probably via a protein
kinase C mediated increase in cytosolic calcium
concentration. Autocrine angiotensin II stimulation is an
important step in the signalling cascade that leads to
stretch-induced cardiomyocyte hypertrophy, and may
play a role in the genesis of stretch-induced
cardiomyocyte apoptosis. There is evidence that stretch
may activate p53, which in turn may enhance expression
of pro-apoptotic Bax, reduce expression of antiapoptotic
Bcl-2, and up-regulate expression of angiotensin II
receptor subtype 1 and angiotensin II genes[18]. On the
other hand, it has recently been shown that angiotensin II,
endothelin (ET)-1, norepinephrine and other G-proteincoupled agonists may induce cardiomyocyte hypertrophy
through generation of ROS, which in turn activates the
transcription factor nuclear factor-kappaB via apoptosis
signal-regulating kinase-1 [19]. As mentioned above,
nuclear factor-kappaB has a clear antiapoptotic effect.
The effects of angiortensin II on hypertrophy and
apoptosis thus appear closely related. However, the
potential importance of angiotensin II stimulation in the
genesis of apoptosis is tempered by experimental
observations that showed that its continuous intravenous
administration for 1 month does not induce apoptosis in
mice, even when the angiotensin II receptor subtype 2 is
over-expressed[20].
In neurohormonal activation, up-regulation of RAAS is
associated with increased plasma levels of ET-1 and other
agonists with potential pro-apoptotic actions, including
TNF-alpha[21], as well as with reduced NO availability.
Although at high concentrations NO may initiate
apoptosis[11], at low concentrations it has been shown to
inhibit apoptosis in various cell types[22,23]. The net effect of
this neurohormonal cocktail on the number of cardiomyocytes, myocardial mass, passive properties and function
results from extremely complex interactions and cannot be
predicted from the effect of individual agonists under
experimental conditions. This is best illustrated by the
clinical observation that significant RAAS activation may
coexist with normal ventricular function for many years in
patients with hypertension. Similarly, patients with hepatic
cirrhosis and high cardiac output (hyperdynamic syndrome)
are exposed to increased sympathetic tone and elevated
levels of angiotensin II and ET-1 for years, with essentially
normal cardiac function. Moreover, it has recently been
observed in cirrhotic rats that the hyperdynamic syndrome
is associated with eccentric hypertrophy with strictly
normal myocardial function, despite severe neurohormonal
activation[24].
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G48
J. Soler-Soler and D. García-Dorado
Table 2 Angiotensin-converting enzyme inhibition: effect on major cardiovascular events
Clinical event
Reinfarction
Readmission for HF
Death or reinfarction
Death or readmission for HF
Death/MI/readmission for HF
Stroke
ACE inhibitors
(n = 6391)
571 (8·9%)
876 (13·7%)
1725 (27·0%)
1962 (30·7%)
2161 (33·8%)
239 (3·7%)
Control
(n = 6372)
703 (11·0%)
1202 (18·9%)
2043 (32·1%)
2354 (36·9%)
2610 (41·0%)
249 (3·9%)
Odds ratio
(95% confidence interval)
0·79 (0·70–0·89)
0·67 (0·61–0·74)
0·77 (0·72–0·84)
0·74 (0·69–0·80)
0·72 (0·67–0·78)
0·96 (0·80–1·15)
P
0·0001
<0·0001
<0·0001
<0·0001
<0·0001
0·63
ACE=angiotensin-converting enzyme; HF=heart failure; MI=myocardial infarction. (Data from Flather et al.[34].)
Angiotensin-converting enzyme inhibitors
Aldosterone receptor inhibition
The rationale behind employing inhibition of aldosterone
receptors in heart failure is based on the fact that ACE
inhibitors do not provide complete, long-term blockade of
the RAAS[38,39]. The Randomized Aldactone Evaluation
Study (RALES) study[40] demonstrated an impressive
Eur Heart J Supplements, Vol. 4 (Suppl G) November 2002
Angiotensin II receptor blockers
The incomplete blockade of the RAAS by ACE inhibitors
has justified intense research in angiotensin II blockers in
heart failure, because they block the system on its distal
side, with direct blockade of the type 1 receptor. Although
the rationale behind such an approach appears favourable,
the recent Evaluation of Losartan in the Elderly (ELITE) II
trial[41] and the Valsartan in Heart Failure Trial
(Val-HeFT)[42] showed no further benefit on mortality when
added to ACE inhibitors. On the other hand, both trials
showed an unexpected finding that is of clinical
significance, namely the possible harmful effect of too
‘intense’ neurohormonal inhibition. Suspicion of such an
effect was raised in a post-hoc analysis that showed that
patients who were on three neurohormonal blockers (ACE
inhibitor, angiotensin II blocker and beta-adrenergic
blocker) did worse than those without beta-blockers. The
definite place of angiotensin II blockers in the management
of heart failure remains to be elucidated. Three very large
trials including more than 30,000 patients, with different
angiotensin II blockers (Candesartan in Heart Failure:
Assessment of Reduction in Mortality and Morbidity
[CHARM], Valsartan in Acute Myocardial Infarction Trial
[VALIANT] and Optimal Trial in Myocardial Infarction
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Angiotensin-converting enzyme (ACE) inhibitors were the
first drugs to show increased survival in patients with
chronic heart failure[31]. In 253 elderly patients (mean age
74 years) with severe heart failure (New York Heart
Association functional class IV) enrolled in the Cooperative
North
Scandinavian
Enalapril
Survival
Study
(CONSENSUS)[31], enalapril administration resulted in a
statistically significant reduction in mortality of 40% (33
deaths in the enalapril arm versus 55 deaths in the placebo
arm) at 6 months. Since that report was published (1987),
many other studies conducted in various heart failure
populations have shown similar results[32,33]. A recent metaanalysis[34] of five major trials of different ACE inhibitors
(i.e. Survival and Ventricular Enlargement [SAVE], Acute
Infarction Ramipril Efficacy [AIRE], Trandolapril Cardiac
Evaluation [TRACE], Studies of Left Ventricular
Dysfunction [SOLVD]-Treatment and SOLVD-Prevention),
including 12,763 patients followed up for an average of
2·5 years of treatment, demonstrated an absolute death
reduction of approximately 6%. Table 2[34] shows the
benefit of ACE inhibition in other major cardiovascular
clinical events.
In all guidelines on the treatment of heart failure, these
data are called upon to support the recommendation of an
ACE inhibitor as a first-choice drug in both symptomatic
and asymptomatic chronic heart failure associated with
systolic left ventricular dysfunction.
As mentioned in the introduction to the present review,
heart failure is a relentless process. Unfortunately, ACE
inhibitors do not stop this progression but just delay the
final outcome[35,36]. It is difficult to calculate the net benefit
of ACE inhibitors in terms of life prolongation, although
some studies suggest a modest additional survival of
0·6–0·9 months[30,35–37].
benefit in terms of global mortality (386 deaths in the
placebo arm versus 284 deaths in the treatment arm) of lowdose spironolactone (mean 26 mg . day – 1) when added to
conventional therapy (95% on ACE inhibitors), after a mean
follow-up period of 24 months. That study included 1663
patients in New York Heart Association functional class III
or IV at the time of enrollment. Accordingly, in all
guidelines, spironolactone is considered a treatment of
choice in severe heart failure.
The effect of aldosterone receptor inhibitors on the
prevention of heart failure progression is not known,
although experimental data indicate an effect on the
myocardial interstitial matrix, which might be of important
clinical significance. At the present time, a study of
mortality in 6000 patients, with a novel selective antagonist
of the aldosterone receptor (eplerenone), is underway (the
Eplerenone’s Neurohormonal Efficacy and Survival Study
[EPHESUS]).
Blocking neurohormonal activation
with the Angiotensin II Antagonist Losartan [OPTIMAAL]),
will clarify this important issue[43]. At present, the use of
these drugs is indicated as monotherapy only in patients
who are intolerant to ACE inhibitors[44].
Beta-adrenergic blockers
Other vasoactive hormone receptors blockers
The neurohormonal activation hypothesis, and the
beneficial effects of RAAS and sympathetic nervous
system blockade stimulated development of blockers of
other vasoactive neurohormone receptors related to the
cardiovascular system (Table 1). Interestingly enough,
preliminary analyses from a number of clinical trials on
mortality have been either neutral or negative (endothelin,
vasopeptidases, TNF-alpha, etc.), despite the fact that pilot
or mechanistic studies had shown clinical and haemodynamic benefit. A typical example of this paradox is the
neutral findings of the recent trial of omapratilat
(n = 5770)[51], despite the fact that this drug had shown
very positive acute and long-term (12 weeks)
haemodynamic and neurohormonal effects in 369
patients[52]. These findings raise the very important issue of
whether there is a limit of blockade of neurohormonal
activation in chronic heart failure, beyond which there is no
further benefit of such interventions. It could well be that
larger is not better.
Conclusion
The results of clinical trials show that some neurohormonal
blockers may improve survival and symptoms, and delay
the progression of heart failure, but they are not able to
prevent or reverse it. There is solid evidence of increased
apoptosis in many situations associated with heart failure
and neurohormonal activation; however, neither the
causative role of neurohormonal activation in the genesis of
apoptosis nor the role of apoptosis in the progression of
heart failure, although likely, have been definitely proven.
The possibility that a reduced rate of apoptosis plays an
important role in the beneficial effect of beta-blockers, ACE
inhibitors and angiotensin II receptor blockers, in patients
with chronic heart failure, is far from confirmed.
Partially supported with a grant CICYT from the Ministerio de
Ciencia y Tecnología. The authors acknowledge the excellent
secretarial work of Gema Santos.
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