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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Usefulness of neurohormonal markers in the diagnosis and prognosis of heart failure

Eulàlia Roig

Institut Clínic del Torax, Hospital Clínic, IDIBAPS – Institut D'Investigacions Biomèdiques August Pi I Sunyer, C/Villarroel 170, Barcelona University, Barcelona 08036, Spain

Corresponding author. Tel: +34 3 2275400 ext. 2035; fax: +34 3 2275454. E-mail address: eroig{at}clinic.ub.es


   Abstract
Top
 Abstract
Introduction
 Neurohormonal activation
 Inflammation and endothelial...
 LV remodelling
 Acknowledgements
 References
 
The recent insights into the pathophysiology of heart failure drawn from studies of mechanisms that lead to ventricular remodelling will be briefly reviewed. Neurohormonal activation has been considered to be an adaptative process activated in response to a fall in cardiac output. Its main goal is to maintain perfusion to the vital organs and assure peripheral perfusion. This activated mechanism is generally adaptive in the short-term and maladaptive over the long-term. There are a number of regulatory peptides and hormones activated in heart failure causing vasoconstriction, water retention and cell growth, and proliferation. There are also counter-regulatory peptides that are released in an attempt to offset the maladaptative actions previously described; their effects being vasodilation, reduction of fluid retention, and inhibition of cell growth and proliferation. Although, a balance between these two opposite hormones and peptides will lead to the stabilization of heart failure, there is now direct evidence that chronic neurohormonal activation makes an important contribution to the progression of heart failure.

The circulating inflammatory cytokines are increased in patients with heart failure. On the basis of a growing body of experimental evidence, cytokines have been associated with negative inotropic effect and left ventricular (LV) remodelling. Expression of the iNOS has been found in myocytes of explanted hearts of patients undergoing heart transplantation. The increased NO within the myocardium can also promote cytotoxic actions inducing myocardial damage, apoptosis, and further disease progression. Moreover, cytokine activation contributes to endothelial dysfunction present in heart failure.

The equilibrium between MMP and TIMP plays an important role preserving the stability of collagen that forms the ECM. It has been pointed out that an imbalance between MMP/TIMP, favouring ECM degradation may facilitate the remodelling process. Supporting this hypothesis, increased expression of enzymes that can contribute to collagen breakdown has been found in myocardial tissue of terminal heart failure patients.

Heart failure is a complex disorder that is still poorly understood. Only a better understanding of the process that mediates LV remodelling will bring new therapeutic approaches.

Key Words: Heart failure • NH activation • LV remodeling


   Introduction
Top
 Abstract
 Introduction
Neurohormonal activation
 Inflammation and endothelial...
 LV remodelling
 Acknowledgements
 References
 
Over the past decade, neurohormonal activation has been considered as the last step in understanding the pathophysiology of heart failure. This hypothesis was based on the great improvement in survival rates achieved with sympathetic and renin–angiotensin system inhibition.1–4 However, despite the angiotensin-converting enzyme-inhibitors (ACE-i) and BB therapy, many patients still have elevated circulating neurohormones that can contribute to further ventricular dilation and progression to end-stage heart failure. In addition to RAS, other systems are also activated in heart failure, such as the immunologic system.5–7 This inflammatory reaction is mediated by cytokine activation that can affect the heart and peripheral circulation. Both neurohormonal and cytokine activation contribute to the endothelial dysfunction present in heart failure.8,9

Most recently, new insights in the pathophysiology of heart failure have been gained from the study of mediators that lead to ventricular remodelling.5 Experimental data have shown that signalling for different factors activated at the tissue level, such as nitric oxide, ACE, and TGF expression, mediates the progression of hypertrophy and fibrosis that contribute to ventricular dilation.10,11

This article will briefly review recent insights into the pathophysiology of heart failure drawn from the experimental and clinical study of mechanisms that lead to ventricular remodelling.


   Neurohormonal activation
Top
 Abstract
 Introduction
 Neurohormonal activation
Inflammation and endothelial...
 LV remodelling
 Acknowledgements
 References
 
The neurohormonal system is activated as a compensatory mechanism when there is a reduction in cardiac output. The decline in stroke volume produces arterial under-filling, which is sensed by the baroreceptors of the great vessels and leads to haemodynamic changes. This haemodynamic response is mediated by sympathetic stimulation, peripheral vasoconstriction, and salt and water retention; these mechanisms are activated to preserve cardiac output and blood pressure in order to assure oxygen delivery to the vital organs.12

These haemodynamic changes are mediated by an increase in circulating levels of hormones such as norepinephrine, angiotensin II, aldosterone, arginine vasopressin, and endothelin.13,14 Besides the circulatory effects of these hormones, they are also very active at tissue level, especially in the myocardium, where they promote hypertrophy and fibrosis. Although neurohormone activation is very effective in maintaining cardiac output at short-term, over a long period of time it increases the work of the heart and by doing so contributes to further deteriorate left ventricular (LV) function. With the activation of these maladaptative hormones there is also activation of peptides and mediators that have the opposite effects. They are released in an attempt to offset the excessive peripheral vasoconstriction and liquid retention present in chronic heart failure. Thus, natriuretic peptides, cytokines, bradykinins, prostaglandins, and adrenomedullin have a vasodilator effect; moreover, at tissue level they inhibit cell growth and proliferation. Usually a balance between these two opposite hormones and peptides will lead to the stabilization of heart failure. However, the balance frequently gives way to a dominant excess of hormones that mediate the maladaptive process, which favours the progression of heart failure.

The SOLVD1 and Consensus2 trials were the source of relevant information about neurohormonal activation in heart failure. In these studies, where ACE-i were used as heart failure therapy for the first time, a relationship between neurohormonal activation and mortality was established. Thus, patients who died during follow-up had higher plasma norepinephrine, angiotensin II, and aldosterone levels, suggesting that neurohormonal activation played an important role in disease progression and death. It also became apparent that the reduction in mortality was mediated by important reductions in circulating neurohormones. These findings help to support the consideration of heart failure as a neurohormonal syndrome.

ACE-i, by lowering angiotensin II formation, increase renin liberation through a lack of negative feed back mechanism. In a sub-study of the SAVE trial,15 where repeated neurohormone determinations were performed, a high proportion of patients had increased plasma renin activity during follow-up. These patients had higher incidence of new coronary events, independently of medical therapy, indicating that despite captopril treatment in some patients there was persistence of neurohormonal activation. Furthermore, several studies have demonstrated an ‘escape’ phenomenon of angiotensin II and aldosterone in spite of ACE-i therapy.16 In these studies, the increase in angiotensin II was associated with higher levels of norepinephrine and aldosterone, indicating a reactivation of the renin–angiotensin and adrenergic systems. Furthermore, an angiotensin ‘escape’ phenomenon was associated with increased morbidity and mortality during follow-up. Recent data from the Val-HeFT trial,17 showed that patients who were under treatment with ACE-i and BB had lower plasma aldosterone and renin plasma levels, whereas norepinephrine values were not modified by the combined therapy. Although blocking the beta receptor protects the heart from the sympathetic activation, if beta-blocker therapy is under-used, high plasma norepinephrine may still activate other neurohormones and contribute to heart failure progression. Moreover, in this study,17 the largest performed with repeated neurohormone determinations, BNP, PRA, and norepinephrine levels above the median of the studied population were associated with higher mortality. Neurohormone changes over time were more important in assessing prognosis; thus, patients with reduced norepinephrine or BNP levels during follow-up had the lowest mortality, whereas patients in whom neurohormone levels increased had worse prognosis. These data suggest that despite the actual medical therapy there are still patients with high neurohormone activation that can contribute to the progression to end-stage heart failure.

Apart from being synthesized in the circulating system, angiotensin II may also be formed locally in the heart by tissue ACE; thereby, binding to the AT-1 receptor, it plays an important role in the development of hypertrophy and fibrosis.18,19 Inhibition of the angiotensin AT-1 receptor was associated with higher blockage of RAS. In large trials where angiotensin receptor antagonists were used as heart failure therapy, only a mild beneficial effect was obtained.20,21 This gives rise to the hypothesis that a more intense blockage of the renin–angiotensin and sympathetic systems may not be possible. Higher dosage of ACE-i or ARA cannot be used because of side effects such as hypotension and worsening renal failure, as demonstrated in these trials.

Higher amounts of circulating natriuretic peptides have also been associated to worse prognosis in heart failure.22,23 Atrial natriuretic peptide is released in the atria in response to atrial stretching, whereas brain natriuretic peptide mainly reflects LV wall stress. Both natriuretic peptides have vasodilator properties; they inhibit aldosterone, AVP, and norepinephrine secretion. Thus, natriuretic peptides have the ability to attenuate neurohormonal activation and promote diuresis. In heart failure, these effects are attenuated because of excessive sympathetic and renin–angiotensin system activation. Although increased values of both natriuretic peptides have been associated with poor prognosis, because of their beneficial effects, it is clear that they do not contribute directly to worsening heart failure. In fact, they are considered sensitive markers of the degree of neurohormone activation and ventricular dysfunction.24 A wide body of evidence has demonstrated the efficacy of BNP in the diagnosis of decompensate heart failure. Several studies with both NT-proBNP and BNP, performed at bedside, have shown a very high negative predictive value.25,26 Thus, in patients presenting with dyspnoea to the ER, heart failure can be ruled out if they have normal BNP values. Furthermore, recent data from clinical investigation proved that plasma levels of BNP can be helpful in assessing prognosis.27 Although BNP still has some limitations, it is considered an accurate marker for heart failure diagnosis; its value in assessing prognosis is still under investigation.


   Inflammation and endothelial dysfunction
Top
 Abstract
 Introduction
 Neurohormonal activation
 Inflammation and endothelial...
LV remodelling
 Acknowledgements
 References
 
The endothelium is the inner layer of the vessels that regulates arterial vasomotor tone. It is a very active layer, with enzyme expression and many receptors. The fact that patients with heart failure have endothelial dysfunction has been known for years. Endothelial dysfunction in these patients is caused by many factors, the most important being the local increase in angiotensin II and endothelin. At the same time, there is reduced expression of the eNOS that impairs flow-mediated vasodilation.28

Endothelin is a potent vasoconstrictor isolated from endothelial cells. Its most important actions in the heart are similar to those of other regulatory mediators such as angiotensin II. By binding the ET-A receptor at the vascular smooth muscle, endothelin has a potent vasoconstrictor response and mediates cell growth and hypertrophy.29 Increased plasma levels of either big-endothelin or endothelin-1 have been associated with higher mortality in heart failure.30–32 Despite its association with worse prognosis, studies with drugs that blocked the endothelin receptors did not improve survival in patients with heart failure,33 in part because of the important side effects of these drugs.

An inflammatory reaction present in heart failure has been identified with increased circulating levels of several cytokines, especially TNF-alpha and IL-6.34 Although initially cytokine activation was thought to be associated with terminal heart failure and cachexia, data from several studies have shown that cytokine levels increase as functional capacity deteriorates.35,36 Cytokines, by promoting iNOS activation, lead to the release of large amounts of NO. As NO has important vasodilator effects it would be beneficial in counteracting vasoconstriction. Thus, like the neurohumoral response, it has the short-term benefit of counterbalancing peripheral vasoconstriction; however, it also activates long-term maladaptive responses, as NO can increase the oxidative stress.8,37

Cytokines are proteins secreted by macrophages and a variety of other cells in response to different stimuli; they contribute to natural immunity and tissue repair. These low molecular weight peptides, by binding to their receptor, activate transcription factors that produce inflammatory mediators such as the iNOS, which is especially relevant when activated in the heart, as NO has negative inotropic effect.38 Data from myocardial tissue obtained from the explanted hearts of patients undergoing heart transplantation showed increased mRNA myocardial expression of TNF, IL-6, and iNOS, indicating that cytokines are locally activated in the myocardium of patients with end-stage heart failure.39 Furthermore, in the animal model, mice that over-expressed TNF developed LV dysfunction and severe dilatation.40 On the basis of these data, new therapies with anti-TNF-alpha effect were designed; however, they fail to improve survival in heart failure.41 Despite these negative results, the role of cytokine activation in heart failure progression is still under investigation, as cytokines play an important role in mediating endothelial dysfunction. Thus, higher TNF-alpha levels have been associated with less endothelial-dependent vasodilation.42 Furthermore, in a recent study where flow-mediated vasodilation was evaluated by high-resolution ultrasound of the brachial artery, a higher degree of endothelial dysfunction was associated with higher mortality during follow-up.43 This is not surprising, as many therapies that improve survival in heart failure, such as ACE-i, carvedilol, and spironolactone, also improve endothelial dysfunction.44 Determining whether the improvement of endothelial dysfunction will improve survival requires further investigation.


   LV remodelling
Top
 Abstract
 Introduction
 Neurohormonal activation
 Inflammation and endothelial...
 LV remodelling
Acknowledgements
 References
 
Ventricular dilation has been associated with worse prognosis in several studies.45 According to Starling's law, dilatation increases stroke volume; whereas, according to Laplace's law, dilation increases wall stress, which worsens the work of the heart. LV remodelling is a silent ongoing process mediated by many factors, such as wall stress, volume or pressure overload, local sympathetic system and renin–angiotensin system activation, growth factors, and many tissue-activated peptides that mediate myocyte hypertrophy and fibrosis10,11 (Figure 1).


Figure 0251
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  		Figure 1 Ventricular remodelling mechanism based on experimental data. With increased wall stress and myocyte damage there is an increase in expression of ACE, which leads to the local angiotensin II and aldosterone formation. Local RAS activation, triggers the activation of growth factors, foetal gene expression, and apoptosis. The activation of these mediators plays a role in hypertrophy and fibrosis formation. Cytokine liberation is also present, activating iNOS that mediates NO liberation. NO increases oxidative stress that causes myocyte damage. ACE, angiotensin, chymase, and other enzymes also increase MMP activation favouring ECM collagen breakdown, and thereby mediating ventricular dilation.

 
Recently, the ECM has been a major focus of investigation, as its degradation contributes to LV remodelling.46 The stability of the collagen that formed ECM depends on the equilibrium between the MMP and TIMP. The regulation of these enzymes is a complex issue because there is a continuous turnover of ECM. In fact, many factors that can either stimulate or reduce their expression have been described. Furthermore, an imbalance between MMP/TIMP has been found in myocardial tissue at end-stage heart failure.47 It is now suggested that at some point of heart failure evolution, locally activated enzymes can increase MMP activity, thereby increasing the collagen breakdown that facilitates the remodelling process.48,49

Besides experimental data, the expressions of enzymes and peptides that play a role in ventricular remodelling have been analysed in myocardial tissue from patients undergoing heart transplantation. Although analysing the explanted heart can only provide information about the terminal phase of heart failure, relevant information could be obtained. Thus, increased mRNA expression of ACE, iNOS, chymase, and oxidative enzymes has been found in myocardial tissue.50,51 Recently, an increase in mast cell density has been found in the myocardium. This finding suggests that degranulation of these cells by liberating active enzymes, such as chymases and triptases, can contribute to collagen breakdown.52,53 In fact, in a recent study performed in patients with heart failure, the increased plasma levels of procollagen III factor, a marker of collagen breakdown, was associated with worse prognosis.54

Heart failure is still a complex syndrome poorly understood. Over the past decade the cell hypertrophy, fibrosis, and changes in ECM have been recognized as important mediators of ventricular remodelling. As knowledge of the pathophysiology of heart failure increases, more previously unknown mediators are discovered. Only better understanding of the process and mechanism that mediates ventricular remodelling will help us find new therapeutic approaches to improve heart failure survival.


   Acknowledgements
Top
 Abstract
 Introduction
 Neurohormonal activation
 Inflammation and endothelial...
 LV remodelling
 Acknowledgements
References
 
The author thanks the efforts in manuscript preparation provided by Elaine Roca.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Neurohormonal activation
 Inflammation and endothelial...
 LV remodelling
 Acknowledgements
 References
 

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