European Journal of Heart Failure

European Journal of Heart Failure 2008 10(2):170-175; doi:10.1016/j.ejheart.2007.12.007

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© 2008 European Society of Cardiology

Acute heart failure as "acute endothelitis" — Interaction of fluid overload and endothelial dysfunction

Paolo C. Colombo^a,*, Duygu Onat^a and Hani N. Sabbah^b

^a Department of Medicine, Division of Cardiology, Columbia University New York, New York, USA
^b Department of Medicine, Division of Cardiovascular Medicine, Henry Ford Health System Detroit, Michigan, USA

^* Corresponding author. Division of Cardiology, New York-Presbyterian Hospital, 622W 168th Street, PH 12-134, New York, NY 10032, USA. E-mail address: pcc2001{at}columbia.edu (P.C. Colombo).

Key Words: Heart failure • Endothelial • Inflammation

Received October 15, 2007; Accepted December 12, 2007

	1. Introduction

Top 1. Introduction 2. Compensatory mechanisms in... 3. The endothelium in... 4. Precipitating factors in... 5. "Systemic endothelitis" in... 6. Renal function and... 7. Cardiac function and... 8. Unifying hypothesis for... 9. Future directions 10. Conclusions References

 
Acute heart failure (AHF) is defined as a change in heart failure (HF) symptoms (i.e. dyspnoea, abdominal bloating, and fatigue) and signs (i.e. pulmonary crackles, jugular vein distension, and peripheral oedema) resulting in a need for urgent therapy. Symptoms and signs of HF are due to elevated left and right ventricular filling pressures with or without low cardiac output [1]. Heart failure symptoms typically worsen a few days (3±2.5 days) before hospital admission [2]. However, recent studies, based on continuous monitoring of intracardiac pressures (i.e. Chronicle, Medtronic Inc.) and of intrathoracic impedance (i.e. OptiVol, Medtronic Inc.), have substantially moved back the clock for the onset of AHF. Congestion (high filling pressures) progressively increases and intrathoracic fluid accumulates, starting 7-14 days before HF signs and symptoms worsen, eventually requiring urgent intravenous therapy [2,3]. What happens during the days that precede overt clinical decompensation? Can congestion itself cause progressive fluid overload, and, if so, is it possible to break this vicious cycle?

Our hypothesis is that "systemic endothelitis", characterized by a boost in endothelial oxidative stress and activation with induction of vasoactive and pro-inflammatory genes, contributes to progressive fluid retention and centralization of blood volume in AHF, through vascular, renal, and neurohormonal mechanisms. The discussion that follows will detail the evidence supporting this hypothesis.

	2. Compensatory mechanisms in chronic heart failure

Top 1. Introduction 2. Compensatory mechanisms in... 3. The endothelium in... 4. Precipitating factors in... 5. "Systemic endothelitis" in... 6. Renal function and... 7. Cardiac function and... 8. Unifying hypothesis for... 9. Future directions 10. Conclusions References

 
Chronic heart failure (CHF) is caused by a loss of ventricular function, and is characterized by various adaptations that include sustained neurohormonal activation and peripheral vasoconstriction. In advanced CHF, the reduction in resting cardiac output is accompanied by marked redistribution of the forward flow to regional circulations [4,5]. This redistribution of limited cardiac output favours vital organs (i.e. heart and brain) over the liver, limbs, skeletal muscles and skin [4,5]. These adaptations, together with medications, sustain the compensated state of CHF. The precise events that trigger the transition from the compensated to the decompensated state of HF remain to be elucidated.

	3. The endothelium in chronic heart failure

Top 1. Introduction 2. Compensatory mechanisms in... 3. The endothelium in... 4. Precipitating factors in... 5. "Systemic endothelitis" in... 6. Renal function and... 7. Cardiac function and... 8. Unifying hypothesis for... 9. Future directions 10. Conclusions References

 
The endothelium is aligned between the blood and tissues. From this strategic position, it generates an impressive number of bioactive molecules such as nitric oxide (NO), prostaglandins, and cytokines, which play a crucial role in the physiological adaptation or pathophysiological dysfunction that regulates and redistributes regional blood flow [6].

Among other factors, the endothelium regulates blood vessel diameter via the release of NO in response to stimulation with agonists such as acetylcholine and bradykinin, and mechanical stimuli such as changes in shear stress, that lead to a relaxation of the underlying vascular smooth muscle cells [7]. Endothelium NO-dependent dilation is decreased in the coronary, skeletal muscle, pulmonary and renal arteries in CHF [8-10]. In the renal arteries, endothelial NO (and vasodilatatory prostaglandins) counteracts the vasoconstrictive effects of angiotensin II, endothelin-1 and catecholamines [10]. Stimulation of endothelial NO release enhances renal perfusion in patients with CHF [11]. Conversely, a reduction in NO bioavailability may further impair renal blood flow. Nitric oxide bioactivity is determined by the balance between synthesis and degradation of NO. The biosynthesis of endothelial NO is catalyzed by constitutively expressed endothelial NO synthase (eNOS) and inducible NO synthase (iNOS), the latter expressed in response to pro-inflammatory stimuli (i.e. cytokines and oxidative stress). Oxidative stress itself, and superoxide specifically, degrades available NO with formation of peroxynitrate, a toxic metabolite that nitrosylates proteins on tyrosine residues [12,13]. Pro-inflammatory stimuli induce a transition in the endothelium from quiescent to activated state by promoting the expression of vasoactive and pro-inflammatory genes such as iNOS and cyclooxygenase-2 (COX-2).

Endothelium-mediated control of the venous vascular tone is also important in HF. Veins represent a low-pressure reservoir that contains >70% of the systemic blood volume [14]. The pronounced capacity of this reservoir implies that relatively small volume changes in the peripheral veins are followed by substantial alterations in central blood volume, and thus in cardiac filling pressures.

	4. Precipitating factors in acute heart failure

Top 1. Introduction 2. Compensatory mechanisms in... 3. The endothelium in... 4. Precipitating factors in... 5. "Systemic endothelitis" in... 6. Renal function and... 7. Cardiac function and... 8. Unifying hypothesis for... 9. Future directions 10. Conclusions References

 
Nonadherence to medical treatments, excessive salt and water intake, respiratory and urinary tract infections, and arrhythmias are traditionally listed as frequent precipitating factors of AHF [15]. However, no overt precipitating factor can be identified in about 50% of patients. The inability to identify a precipitating factor responsible for clinical deterioration may relate to the severity of impairment in functional status at baseline, and thereby to the ease of destabilization. It may also reflect a tendency by physicians and patients to focus their attention only on the last few days that precede the index hospitalisation. Recent data from continuous monitoring of intrathoracic impedance and ventricular filling pressures suggest that one may be better served by focusing on the preceding weeks when fluid retention begins to take place [2,3].

From a vascular perspective, it is interesting that systemic infections, a recognized trigger of AHF, can cause endothelial dysfunction [16]. In a study of 600 children, Charakida et al. reported impairment in endothelium-dependent vasodilation during active or after recent acute infections [17]. The association of acute infections with endothelial dysfunction may also account for the observation that acute infections increase the short-term risk of cardiovascular events [18].

	5. "Systemic endothelitis" in acute heart failure

Top 1. Introduction 2. Compensatory mechanisms in... 3. The endothelium in... 4. Precipitating factors in... 5. "Systemic endothelitis" in... 6. Renal function and... 7. Cardiac function and... 8. Unifying hypothesis for... 9. Future directions 10. Conclusions References

 
We recently reported a particularly severe impairment in endothelium NO-dependent vasodilation in patients hospitalised with AHF [19,20]. Using a novel approach that involves sampling of venous endothelial cells and quantification of protein expression by quantitative immunofluorescent analysis [21,22], we observed an increase in endothelial oxidative stress that eventually justifies this decline in vascular NO bioactivity (Fig. 1) [20]. The increase in venous endothelial oxidative stress partially subsided with clinical improvement during the index hospitalisation. Transient endothelial activation was also present in these patients, as evidenced by an increase in endothelial iNOS and COX-2 expression. The resulting increase in NO and prostaglandin production may represent an attempt to counteract oxidative stress-mediated vasoconstriction and sodium retention. This compensatory mechanism may fail for opposite reasons: it may be insufficient to counteract overwhelming oxidative stress, or it may be excessive, causing profound vasodilation, thus hindering preferential distribution of limited cardiac output to essential organs. Since vasoconstriction (i.e. high systemic vascular resistance) and sodium retention are typically present in patients hospitalised with AHF, the former explanation appears more convincing [23]. In summary, "acute endothelitis", as characterized by enhanced endothelial oxidative stress and activation, occurs in veins at the time of clinical decompensation. Enhanced endothelial oxidative stress and activation were also evident in the arteries of five patients with AHF who required an arterial line for continuous blood pressure monitoring [22]. Thus, "acute endothelitis" is present in veins and arteries in AHF, and, as such, is manifested "systemically".

View larger version (22K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 1 Increased endothelial oxidative stress and activation in patients with AHF. Quantitative analysis of nitrotyrosine immunoreativity (cellular marker of oxidative stress) (A), COX-2 (B), eNOS (C) and iNOS (D) protein expression was performed in venous endothelial cells of patients with decompensated AHF before, and after return to a steady compensated state, and in endothelial cells of age-matched healthy subjects. Results for nitrotyrosine, COX-2, eNOS and iNOS are expressed as ratios to average pixel count in human umbilical vein endothelial cells (HUVEC) (reference slides). *P<0.01 vs. decompensated AHF; P<0.05 vs. decompensated AHF; P<0.01 vs. healthy subjects; P<0.05 vs. healthy subjects. (Modified from Colombo et al. [20]).

 
Two major issues remain to be addressed to further confirm the hypothesis of "systemic endothelitis" that directly impact on the pathophysiology of AHF. First, a direct cause-effect relationship needs to be established between the development of "systemic endothelitis" and the onset of fluid accumulation in AHF. Second, the mechanisms that promote "systemic endothelitis" need to be identified.

Unfortunately, the transition from compensated CHF to AHF is not readily amenable to investigation for logistic reasons. Patients with compensated CHF are ambulatory, and they usually look for medical attention only several hours to days after the onset of clinical symptoms, thus several days to weeks after fluid retention begins to take place. Therefore, our initial studies focused on the transition from the decompensated to the compensated state of HF, which is amenable to investigation since patients are available for close monitoring in a hospital setting. Novel diagnostic systems for continuous monitoring of intracardiac pressures (i.e. Chronicle, Medtronic Inc.) and of intrathoracic impedance (i.e. OptiVol, Medtronic Inc.) may allow early detection of congestion, thereby offering investigational opportunities to clarify the role of "systemic endothelitis" in the pathophysiology of AHF [2,3].

Regarding the mechanisms that promote "endothelitis", biochemical and biomechanical stimuli seem to play a central role [6]. Plasma levels of angiotensin II, tumour necrosis factor- (TNF-), and interleukin-1β increase as symptoms worsen in patients with advanced HF [24]. Cytokines activate NAD(P)H oxidase, thereby increasing superoxide production [25-27]. Superoxide scavenges NO with formation of peroxynitrate. Serum levels of TNF- inversely correlate with endothelium NO-dependent vasodilation in patients with CHF, thus supporting a direct effect of circulating cytokines on NO bioavailability [28]. Biomechanical stimuli are also important in HF. Fluid retention increases arterial and venous hydrostatic pressure. Sustained endothelial stretch increases superoxide production [29-31]. Oxidative stress, in turn, promotes endothelial cell activation by inducing the expression of several vasoactive and pro-inflammatory genes [32].

We recently studied the venous endothelium in normal dogs and in CHF dogs with left ventricular systolic dysfunction produced by coronary microembolization. Both groups had normal venous pressures (8 mmHg). Normal dogs were studied at baseline and 1 h after fluid load resulting in an increase in venous pressure to >20 mmHg. Endothelial mRNA expression of iNOS and COX-2, TNF- and receptor for advanced glycation end products (RAGE) (an activator of NAD(P)H oxidase [33]) were increased in dogs with CHF compared to normals. In normal dogs, fluid load increased iNOS, COX-2, TNF-, and RAGE expression to levels that approached those of dogs with compensated CHF [34].

We can thus conclude that both biochemical (i.e. the pro-inflammatory state of HF) and biomechanical stimuli (i.e. vascular stretch caused by an increase in hydrostatic pressure) are sufficient to induce "endothelitis".

	6. Renal function and congestion in acute heart failure

Top 1. Introduction 2. Compensatory mechanisms in... 3. The endothelium in... 4. Precipitating factors in... 5. "Systemic endothelitis" in... 6. Renal function and... 7. Cardiac function and... 8. Unifying hypothesis for... 9. Future directions 10. Conclusions References

 
"Vasomotor nephropathy" with progressive sodium and water retention characterizes AHF. "Vasomotor nephropathy" is defined as transient renal dysfunction related to a perfusion mismatch of the afferent/efferent glomerular arteries due to vascular (i.e. NO and prostaglandins), haemodynamic (i.e. intravascular pressures), neural (i.e. sympathetic) and humoral (i.e. Renin-Angiotensin-Aldosterone System (RAAS)) mechanisms, all leading to fluid retention [1].

From a vascular standpoint, a reduction in endothelial NO bioavailability and/or an imbalance in prostaglandin production may cause vasoconstriction, and reduce renal blood flow and sodium excretion [10]. From a haemodynamic standpoint, both arterial and venous pressures regulate sodium excretion in the kidneys. Perception of inadequate filling of the arterial circulation triggers direct, vascular, neural and humoral mechanisms that reduce sodium excretion. The concept of a reduction in effective plasma volume has directed attention away from the fact that both total plasma volume and venous pressure are commonly increased in AHF [35,36]. This observation is important since venous pressure modulates sodium excretion too. Unilateral renal vein constriction decreases sodium excretion in dogs, an effect more prominent in volume-expanded animals [37]. An increase in renal venous pressure, while arterial pressure is unchanged, decreases sodium excretion in isolated perfused kidney in dogs [36]. The mechanisms by which increased renal venous pressure alters sodium handling in the kidneys are poorly defined. Of interest, both oxidative stress (and peroxynitrates) and TNF-, which are increased in advanced HF, have been shown to reduce renal sodium excretion [38,39].

	7. Cardiac function and congestion in acute heart failure

Top 1. Introduction 2. Compensatory mechanisms in... 3. The endothelium in... 4. Precipitating factors in... 5. "Systemic endothelitis" in... 6. Renal function and... 7. Cardiac function and... 8. Unifying hypothesis for... 9. Future directions 10. Conclusions References

 
As previously summarized by Gheorghiade et al., high ventricular filling pressures may negatively impact cardiac function, by causing subendocardial ischaemia, left ventricular remodelling, impairment of cardiac venous drainage from coronary veins, and a lower threshold for arrhythmias [40]. The resulting decrease in cardiac output may further impair renal perfusion and function, thereby causing additional fluid retention. Of note, the cardiac endocardium is structurally identical to and in continuity with the vascular endothelium, and is thus likely involved in the process of "systemic endothelitis".

	8. Unifying hypothesis for the pathophysiology of acute heart failure

Top 1. Introduction 2. Compensatory mechanisms in... 3. The endothelium in... 4. Precipitating factors in... 5. "Systemic endothelitis" in... 6. Renal function and... 7. Cardiac function and... 8. Unifying hypothesis for... 9. Future directions 10. Conclusions References

 
In patients with compensated CHF, an inflammatory insult of varying aetiology (i.e. infections, non-compliance with diet or medications), acting through biochemical or biomechanical stimulation, may induce or worsen "systemic endothelitis", as characterized by enhanced endothelial oxidative stress and activation (Fig. 2). "Systemic endothelitis" may, in turn, offset preferential distribution of limited cardiac output to vital organs, most importantly, to the kidneys. Furthermore, "systemic endothelitis" may lead to constriction of capacitance veins, thus centralizing blood volume. Kidney underperfusion may trigger direct, vascular, neural and humoral mechanisms that lead to sodium and water retention. Veins progressively engorge, and further constrict via a stretch-mediated increase in vascular oxidative stress. In the kidneys, vascular congestion and activation of the stretched endothelium, now itself a source of oxidative stress and pro-inflammatory cytokines, may cause additional fluid retention. In the heart, congestion further impairs systolic and diastolic function. The resulting decrease in cardiac output is sensed by the kidneys, and results in additional fluid retention. Subsequently, when the initial inflammatory insult subsides, it may be too late. Vicious cycles that link progressive fluid overload to "systemic endothelitis" and to cardiac dysfunction are already in place. Symptoms will eventually occur or worsen after a few weeks of progressive fluid retention and centralization of blood volume. Increasing dyspnoea and anxiety may then trigger a catecholamine surge that further increases the arterial and venous tone, thus resulting in additional centralization of blood volume. The clinical status may, thereby, rapidly deteriorate during the last few days that precede hospital admission.

View larger version (33K): [in this window] [in a new window] [Download PowerPoint slide]   Fig. 2 "Systemic endothelitis" in the pathophysiology of AHF. An inflammatory insult of biochemical (i.e. respiratory and urinary infections, non-compliance with medications) or biomechanical nature (i.e.. fluid retention due to non-compliance with medications or diet) causes "systemic endothelitis", that in turn, through vascular, renal and neurohormonal mechanisms, leads to fluid retention. Congestion and activation of the stretched endothelium, may itself worsen "systemic endothelitis". "Systemic endothelitis" also results in endothelium-mediated constriction of capacitance veins, thus causing centralization of blood volume. Concurrently, congestion causes worsening of cardiac function, that in turn, through vascular, renal and neurohormonal mechanisms, leads to additional fluid retention, thereby creating a second vicious cycle. Progressive fluid overload and centralization of blood volume may ultimately lead to clinical decompensation.

 

	9. Future directions

Top 1. Introduction 2. Compensatory mechanisms in... 3. The endothelium in... 4. Precipitating factors in... 5. "Systemic endothelitis" in... 6. Renal function and... 7. Cardiac function and... 8. Unifying hypothesis for... 9. Future directions 10. Conclusions References

 
"Systemic endothelitis", characterized by a boost in endothelial oxidative stress and activation with induction of vasoactive and pro-inflammatory genes, offers a new insight into the pathophysiology of AHF. Novel diagnostic systems for continuous monitoring of intracardiac pressures and intrathoracic impedance represent an investigational opportunity to clarify the role of "systemic endothelitis", and, in general, of the cardiovascular and renal events that occur in the early phase of AHF, several days to weeks before clinical presentation. Early detection and better understanding of the pathophysiology of AHF, may allow future treatment strategies to switch from the current "rescue mode" of late intravenous interventions (i.e. inotropes, diuretics), to a "preventive mode" of oral interventions (i.e. reinforce compliance to medications and diet, diuretics, anti-oxidants) that may abort AHF before the development of clinical decompensation.

	10. Conclusions

Top 1. Introduction 2. Compensatory mechanisms in... 3. The endothelium in... 4. Precipitating factors in... 5. "Systemic endothelitis" in... 6. Renal function and... 7. Cardiac function and... 8. Unifying hypothesis for... 9. Future directions 10. Conclusions References

 
"Systemic endothelitis" is present in patients with AHF, and may be responsible, albeit in part, for the acute transition from compensated to decompensated HF. The path is one of moving from an initial inflammatory insult into vicious cycles of progressive vascular, cardiac and renal impairment, all contributing to congestion. Our "vasculocentric" view is aimed at complementing rather than replacing the more traditional "cardiocentric" vision, since both systems (the vasculature and the heart) appear to be involved in the events that trigger and sustain AHF. Considerable additional work is needed to further support the validity of this concept as key mediator of AHF syndrome.

	References

Top 1. Introduction 2. Compensatory mechanisms in... 3. The endothelium in... 4. Precipitating factors in... 5. "Systemic endothelitis" in... 6. Renal function and... 7. Cardiac function and... 8. Unifying hypothesis for... 9. Future directions 10. Conclusions References

 

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