European Journal of Heart Failure 10 (2008) 165 – 169

www.elsevier.com/locate/ejheart

Review
Fluid overload in acute heart failure — Re-distribution and other
mechanisms beyond fluid accumulation
Gad Cotter a,⁎, Marco Metra b , Olga Milo-Cotter a , Howard C. Dittrich c , Mihai Gheorghiade d
a
Momentum-Research Inc, Durham, NC, USA
b
University of Brescia, Brescia, Italy
c
University of California, San Diego, California, USA
d
Division of Cardiology, Northwestern University, Chicago, IL USA
Received 3 October 2007; received in revised form 9 January 2008; accepted 15 January 2008

Abstract

Although fluid overload is one of the most prominent features of acute heart failure (AHF), its mechanism remains challenging, due to the
lack of consistent data from prospective studies. Traditionally, fluid overload was thought to be mainly the result of either increased intake of
fluid and salt or non-adherence with diuretic therapy. However, recent data showed little weight change before or during an AHF event
suggesting that in many cases fluid overload is caused by other mechanisms such as fluid redistribution and neurohormonal or inflammatory
activation. Redistribution may be the result of a combined vascular and cardiac process reducing capacitance in the venous system (and hence
increasing preload) and increasing arterial stiffness and resistance (and hence afterload). When these vascular processes occur acutely and are
superimposed on reduced cardiac function; fluid is redistributed to the lungs instigating pulmonary congestion. In this paper we elaborate on
this possible pathophysiological mechanism and review its potential causes and amplifiers.
© 2008 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.

Keywords: Fluid overload; Heart failure

1. Introduction
Heart failure is a leading cause of morbidity and mortality
[1]. Recent registries and clinical trials have allowed a better
characterization of the clinical profile of patients with AHF
[2–5]. Fluid overload, especially in the form of pulmonary
congestion confirmed by chest x-ray is found in the majority
of patients. Based on the assumption that fluid overload is
the result of fluid accumulation, correction of volume status
using diuretics, to reduce the total volume of fluid in the
body, is recommended by European and American Heart
Failure Societies as a first line therapy [6–8]. Indeed, 93% of
patients received diuretic therapy in the Euro Heart Survey II
(EHFS II) [5], and 87% of patients enrolled in the ADHERE
registry received diuretic therapy [3,4].
2. Sub-classification of the AHF syndrome — acute
cardiovascular vs decompensated cardiac failure
Two general types of AHF syndromes – acute cardio-
vascular (hypertensive) and acute decompensated (cardiac)
failure – have been previously suggested [9,10]. Although in
most cases no “pure” presentation is encountered, in many
patients one of those types of AHF predominates:
2.1. Acute cardiovascular (hypertensive) failure

This rapidly progressive disorder is characterized by high

⁎ Corresponding author. Momentum-Research Inc. (MRI), Suite 802, blood pressure accompanied by severe acute dyspnoea. It is
3100 Tower Boulevard, Durham, NC, 27707, USA. commonly encountered in emergency settings and when
E-mail address: gadcotter@momentum-research.com (G. Cotter). extreme (pulmonary oedema with systemic oxygen
1388-9842/$ - see front matter © 2008 European Society of Cardiology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.ejheart.2008.01.007
166 G. Cotter et al. / European Journal of Heart Failure 10 (2008) 165–169
desaturation), may be life threatening. This type of AHF is
more common in the elderly, women, and patients with
history of hypertension, and is accompanied by relatively
preserved ejection faction [11]. Acute cardiovascular failure
is the more frequent clinical presentation for patients with a
first episode of AHF (generally referred to as de novo AHF).
2.2. Acute decompensated (cardiac) failure
This syndrome is characterized by milder and more
slowly worsening symptoms; infrequent pulmonary oedema,
frequent jugular vein congestion, hepatomegaly, peripheral
oedema, signs of renal and hepatic dysfunction, poor
peripheral perfusion with azotaemia and mental obtundation.
Blood pressure is usually in the normal or low range rather
than elevated. Patients generally have a history of HF and are
more frequently younger and male. Precipitating factors are
commonly detected, including non-adherence with diet and
heart failure treatment, concomitant pharmacologic therapy
(i.e. anti-inflammatory agents, negative inotropic agents),
concomitant infection, or decreased ventricular contractility
due to ongoing myocardial injury (e.g., ischaemia). Acute
decompensated cardiac failure has a poor prognosis with
high in-hospital and short-term (3–4 months) mortality.
3. Fluid redistribution vs. fluid accumulation
A few recent studies support the notion that fluid ac-
cumulation does not play a pivotal role in most AHF patients.
Verwey et al. [12] demonstrated that patients with chronic
heart failure monitored closely by invasive and non-invasive
measures had worsening of AHF and increase in pulmonary
pressure, days to weeks before weight gain was first
observed. Moreover, even when weight gain did occur it
was only in the range of about 2 kg. Those results were
confirmed by Lewin et al. [13], who demonstrated that weight
gain did not differ, in a prospective cohort of patients with
chronic HF, between those who developed acute heart failure
and those who did not. The same findings were observed in
the MIRACLE study (Bourge RC; personal communication).
It is suggested that in patients with predominantly acute
cardiovascular failure, fluid overload mostly in the form of
pulmonary congestion, is caused by fluid redistribution rath-
er than by fluid accumulation. Increased vascular resistance/
stiffness may lead to both reduced capacitance in the large
veins and increased arterial resistance. The decrease in
capacitance in large veins will lead to increased venous
return and heightened preload. The increased stiffness and
resistance in the arterial bed leads to increased afterload.
Cardiac dysfunction may also play a central role in this type
of AHF. The hearts of these patients may have a reduced
contractile reserve and probably increased stiffness, leading
to decreased compliance. Hence, the heart cannot effectively
accommodate a change in fluid balance imposed by both pre-
and after-load increase, leading to increased intracardiac
pressures transmitted back to the pulmonary veins and lungs.
A few recent registries and studies support this hypo-
thesis. First, patients admitted with AHF have high blood
pressure. In registries documenting blood pressure of patients
with AHF, it was found to be high [2–4]; and in a recent study
that recorded the first blood pressure before any treatment
was administered it was reported to be extremely high [14].
This increased blood pressure subsides rapidly with treat-
ment and almost normalizes in less than 24 h from admission
[15]. Lewin et al. [14] comparing patients followed in out-
patient clinics who developed AHF versus those who did not,
only found that weight gain did not differ between the two
groups; however, the most predictive change in patients
symptoms and signs prior to an AHF episode was an increase
in blood pressure. This significant increase in blood pressure
prior to and during an AHF event may be explained by
increased vascular resistance/stiffness. In a small study that
followed haemodynamic changes in patients who developed
AHF versus those who did not [12], the main finding was an
increase in vascular resistance superimposed on reduced and
deteriorating cardiac contractility in patients who later
developed AHF. In support of such vascular mechanism in
AHF, Balmain and McMurray [16] have recently published
the results of a non-invasive study assessing arterial
compliance and venous capacitance in patients with HF
and preserved versus reduced systolic function and controls.
Patients with acute cardiovascular failure commonly have
preserved systolic function and hence generally resemble
those with HF and preserved systolic function. In the reported
study, patients with HF and preserved systolic function had
decreased arterial compliance as well as venous capacitance
as compared to the other groups, again supporting a role for
these abnormalities in HF, especially when with character-
istics similar to those of acute cardiovascular failure [17].
Combined ventricular and arterial stiffening, beyond that
associated with aging and/or hypertension, has also been
shown by Kamaguchi et al. in patients with HF and preserved
ejection fraction [17]. Finally, studies examining the effect of
vasodilators in patients with AHF have shown beneficial
effects. In a small study, we compared two strategies early in
the treatment of patients with AHF — high dose nitrates with
low dose diuretics versus low dose nitrates with high dose
diuretics [18]. The study showed a clear advantage of the
vasodilator strategy on rate of improvement in oxygen
saturation and prevention of mechanical ventilation, infarc-
tion and death. In the VMAC study [19], a substantial
improvement in patients' symptoms was achieved by more
effective vasodilatation with nesiritide.
On the other hand, some studies have suggested a dis-
crepancy between weight loss per se and symptom improve-
ment or outcome in patients with AHF. In the IMPACT-HF
study and registry [10], the degree of weight loss during an
AHF admission was not associated with the degree of
improvement in fatigue, paroxysmal nocturnal dyspnoea, or
rest dyspnoea. Only orthopnoea and dyspnoea on exercise
improved more in patients who lost more weight. A greater
degree of weight loss was not associated with a reduction in
 G. Cotter et al. / European Journal of Heart Failure 10 (2008) 165–169
recurrent HF or death at 60 days. In the EVEREST study, the
administration of the aquaretic tolvaptan led to a significant
reduction in weight. However, this did not translate into a
substantial and sustained improvement in patients’ symptoms
or outcome.
As stated previously, vascular mechanisms have a
relatively more pronounced role in cardiovascular versus
decompensated cardiac failure [20]. However, on aggregate
these data suggest that vascular constriction – arterial and
possibly venous – occurs in patients with AHF and hence its
relief may improve patients' symptoms. On the other hand,
fluid loss per se is not related to significant improvements in
symptoms and outcome in most patients. These data suggest
that the mechanism of fluid overload in most AHF patients
may relate to redistribution rather than simple accumulation.
4. Other mechanisms contributing to fluid overload and
redistribution
The combination of decreased arterial compliance and
cardiac function commonly observed in AHF leads to arterial
under-filling. The hypothesis of arterial under-filling was first
proposed in the late 80s by Schrier and colleagues and
examined body fluid status in different oedematous disorders,
including heart failure, cirrhosis and pregnancy [21,22]. The
kidney is one of the most important organs and responds to
this process with sodium and water retention. Arterial under-
filling at the level of the carotid sinus and aortic arch,
activates the sympathetic nervous system with a subsequent
cascade of physiological responses, including an increase in
peripheral and renal vascular resistance, non osmotic release
of AVP and AQP2-mediated renal water retention, catecho-
lamine release and renin–angiotensin–aldosterone system
(RAAS) activation.
4.1. Renin–angiotensin–aldosterone system
The RAAS system is stimulated in patients with heart
failure. Angiotensin, aldosterone and renin levels are
increased in these patients. Activation of the RAAS system
leads to vasoconstriction, thus amplifying the above men-
tioned core processes of AHF as well as fluid accumulation,
both directly and through stimulation of intermediary
mediators such as aldosterone. The importance of this system
in HF is emphasized by the fact that blocking any of its
components (ACE inhibitors, AT II antagonists, aldosterone
blockers) has resulted in improved outcome of patients with
HF mainly by preventing the occurrence of AHF.
4.2. Natriuretic peptide resistance
Inability to respond appropriately to escalating levels of
natriuretic peptides has been reported in patients with heart
failure [23,24]. Elevated plasma levels of BNP and NT-
proBNP are now widely used as a sensitive diagnostic mark-
er in heart failure patients.
167
Despite the increased production of natriuretic peptides,
subjects with HF fail to increase the glomerular filtration rate
and urinary sodium excretion. Several mechanisms have
been proposed to explain this natriuretic peptide resistance.
These include down regulation of renal receptors for na-
triuretic peptides, increased endopeptidase activity, secretion
of inactive natriuretic peptide and enhanced proximal tubular
sodium reabsorption, which leads to diminished delivery of
sodium to the distal nephron which is the site of natriuretic
peptide action. This natriuretic peptide resistance may ex-
plain some of the fluid overload as well as increased vascular
resistance observed in AHF.
4.3. Arginine vasopressin release
In the early 80s, Szatalovicz et al. first reported in-
appropriately elevated levels of plasma arginine vasopressin
(AVP) in hyponatraemic heart failure patients [25]. This non-
osmotic release of vasopressin, mediated by baroreceptors,
overrides the osmotic regulation of AVP and is one of the
leading factors for hyponatraemia in patients with heart
failure. Vasopressin stimulation of V2 receptors with changes
of AQP2 water channels, results in the passive reabsorption
of water. In addition to activation of the V2 water channels,
AVP has also been reported to activate V1a receptors in the
vascular smooth muscle, with constriction of coronary
vessels and stimulation of cardiac myocyte proliferation
[26,27]. These data suggest a role for vasopressin in the fluid
overload observed in AHF. However, as mentioned above,
the use of the vasopressin antagonist tolvaptan did not result
in improved outcome in patients with AHF.
4.4. Inflammatory activation
Inflammatory activation has been documented repeated-
ly in patients with HF and especially in AHF [28]. In-
flammatory activation may have a role in heart failure by both
contributing to vascular dysfunction and magnifying fluid
overload. This issue is reviewed by Colombo in detail [29];
however, one important aspect of inflammatory activation
relates to its contribution to volume overload without fluid
accumulation. The amount of fluid in the pulmonary inters-
titium and alveoli is tightly controlled by an active process of
re-absorption. Recent studies have shown [30] that inflam-
mation interferes with this process. Hence, inflammatory
activation per se may lead to pulmonary fluid overload des-
pite no increase in total body fluid.
4.5. Progressive renal dysfunction
Chronic renal failure secondary to diabetes, hypertension,
and atherosclerosis is common among patients with heart
failure. In addition to these “traditional” risk factors, which can
cause irreversible changes such as permanent structural
abnormalities or reversible changes like vasomotor nephro-
pathy, heart failure itself may accelerate development of renal
168 G. Cotter et al. / European Journal of Heart Failure 10 (2008) 165–169
dysfunction. In the setting of CHF the most common type of
renal dysfunction is pre-renal azotaemia [31]. Reduction in
renal perfusion and the consequent fall in GFR, leads to reflex
activation of the RAAS with tubular reclamation of salt and
water. In addition, some of the neurohormonal and inflamma-
tory activation commonly observed in HF patients probably
also contributes to renal dysfunction. The result is reduced
functional, but to some degree also structural, kidney
dysfunction with hypoxic and vasoconstrictive injury which
may also lead to tubular necrosis. Relatively recent data
suggest that the high renal venous pressure contributes to this
vasomotor nephropathy and further amplifies renal dysfunc-
tion in HF [32].Finally, in patients with combined HF and renal
failure it is possible that diuretic therapy by itself contributes to
some renal impairment, although there is no direct evidence
from prospective randomised studies to support this claim.
Progressive renal dysfunction, by inducing salt and fluid
retention as well as further neurohormonal and inflamma-
tory dysfunction, stimulates the HF process inducing an
important vicious cycle — one of the key contributors to
HF exacerbation.
In support of this concept, recent preliminary studies
examining the effect of adenosine blockers in AHF have
shown promising results. These agents block the tubuloglo-
merular feedback mechanism (TGF), preventing adenosine
mediated renal arterial vasoconstriction in response to diu-
resis. This mechanism is reviewed in detail in a paper by
Vallon et al. [33]. In a preliminary study utilizing different
doses of the adenosine A1 antagonist rolofillyne, trends were
observed towards an improvement in dyspnoea and a
reduction in worsening heart failure and renal impairment
[34]. Hence, it is possible that protecting the kidneys may be
an important target in treating AHF with fluid overload.
4.6. Medications
Non-selective and selective non-steroidal anti-inflam-
matory drugs are commonly used to manage pain and in-
flammation. They attenuate prostaglandin-mediated
mechanisms responsible for modulating renal function,
including renal vascular tone and electrolyte and water
excretion. Fluid and salt retention is also linked to the
blunting of clinical response to diuretic therapy. A recently
published article [35] reported a similar incidence of oedema
with celecoxib compared to diclofenac, but a significantly
lower incidence with ibuprofen.
The thiazolidinediones (TZDs) are a relatively new class
of oral agents for the treatment of type 2 diabetes. The major
adverse effects of the currently available TZDs, rosiglitazone
and pioglitazone, are weight gain, oedema and anaemia. The
exact mechanism of this adverse effect is unknown; pro-
posed mechanisms include decreased free water clearance,
increased sodium reabsorption and increased endothelial
permeability. Congestive heart failure and pulmonary oe-
dema have only recently been recognized as significant
adverse effect of TZDs. The majority of cases of heart failure
were reported in patients with previous history of CHF, and
when TZDs were used as a combination therapy with insulin.
Current recommendations advise against the use of this class
of drug in patients with NYHA class II–IV heart failure.
5. Summary
The pathophysiology of volume overload in patients with
AHF remains challenging, due to the lack of consistent data
from prospective studies and the resulting lack of formal,
evidence-based treatment guidelines. Recent studies have
suggested minimal weight changes before, during and after
an AHF episode. On the other hand, vascular constriction of
both the arterial and venous beds seems to occur commonly
in patients with AHF, particularly in the cardiovascular type,
and its relief has been shown to improve symptoms of fluid
overload and possibly outcome. Hence, it is possible that the
main pathophysiological mechanisms of fluid overload in
AHF are related to fluid re-distribution rather than ac-
cumulation. This redistribution is induced by vascular
mechanisms as well as neurohormonal and inflammatory
activation, renal dysfunction and inappropriate use of some
medications. The end result of these processes is that fluid
accumulates in some peripheral organs and especially in the
lungs, causing the AHF symptoms of volume overload.
Better understanding of the pathophysiology of fluid over-
load may enhance our ability to develop effective treatments
that will improve the outcome of AHF.
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