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European Journal of Heart Failure 2008 10(2):165-169; doi:10.1016/j.ejheart.2008.01.007
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© 2008 European Society of Cardiology

Fluid overload in acute heart failure — Re-distribution and other mechanisms beyond fluid accumulation

Gad Cottera,*, Marco Metrab, Olga Milo-Cottera, Howard C. Dittrichc and Mihai Gheorghiaded

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

* Corresponding author. Momentum-Research Inc. (MRI), Suite 802, 3100 Tower Boulevard, Durham, NC, 27707, USA. E-mail address: gadcotter{at}momentum-research.com (G. Cotter).


   Abstract
Top
 Abstract
1. Introduction
 2. Sub-classification of the...
 3. Fluid redistribution vs....
 4. Other mechanisms contributing...
 5. Summary
 References
 
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.

Key Words: Fluid overload • Heart failure

Received October 3, 2007; Revised January 9, 2008; Accepted January 15, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Sub-classification of the...
 3. Fluid redistribution vs....
 4. Other mechanisms contributing...
 5. Summary
 References
 
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
Top
 Abstract
 1. Introduction
 2. Sub-classification of the...
3. Fluid redistribution vs....
 4. Other mechanisms contributing...
 5. Summary
 References
 
Two general types of AHF syndromes - acute cardiovascular (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 blood pressure accompanied by severe acute dyspnoea. It is commonly encountered in emergency settings and when extreme (pulmonary oedema with systemic oxygen 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
Top
 Abstract
 1. Introduction
 2. Sub-classification of the...
 3. Fluid redistribution vs....
4. Other mechanisms contributing...
 5. Summary
 References
 
A few recent studies support the notion that fluid accumulation 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 rather 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 hypothesis. 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 treatment 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 characteristics 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, infarction 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 discrepancy between weight loss per se and symptom improvement 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 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
Top
 Abstract
 1. Introduction
 2. Sub-classification of the...
 3. Fluid redistribution vs....
 4. Other mechanisms contributing...
5. Summary
 References
 
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, catecholamine 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 mentioned 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 marker in heart failure patients.

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 natriuretic 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 explain 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 inappropriately 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 repeatedly in patients with HF and especially in AHF [28]. Inflammatory 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 interstitium and alveoli is tightly controlled by an active process of re-absorption. Recent studies have shown [30] that inflammation interferes with this process. Hence, inflammatory activation per se may lead to pulmonary fluid overload despite 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 nephropathy, heart failure itself may accelerate development of renal 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 inflammatory 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 dysfunction 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 inflammatory 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 tubuloglomerular feedback mechanism (TGF), preventing adenosine mediated renal arterial vasoconstriction in response to diuresis. 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-inflammatory drugs are commonly used to manage pain and inflammation. 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; proposed mechanisms include decreased free water clearance, increased sodium reabsorption and increased endothelial permeability. Congestive heart failure and pulmonary oedema 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
Top
 Abstract
 1. Introduction
 2. Sub-classification of the...
 3. Fluid redistribution vs....
 4. Other mechanisms contributing...
 5. Summary
References
 
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 accumulation. 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 overload may enhance our ability to develop effective treatments that will improve the outcome of AHF.


   References
Top
 Abstract
 1. Introduction
 2. Sub-classification of the...
 3. Fluid redistribution vs....
 4. Other mechanisms contributing...
 5. Summary
 References
 

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Acute heart failure syndromes.
J. Am. Coll. Cardiol., February 17, 2009; 53(7): 557 - 573.
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