European Heart Journal Supplements (2002) 4 (Supplement D), D3-D 11

Neurohormonal modulation in chronic heart failure R. Ferrara 1, F. MastrorillP, G. PasanisP, S. CensP, N. D'Aiello 1, A. FucilP, M. ValgimiglP, 2 and R. FerrarP 1Cardiovascular Research Center, "S. Maugeri'Foundation, Gussago, Brescia, and 2Chair of Cardiology, University of Ferrara, Arcispedale S. Anna, Ferrara, Italy

spirouolactone in CHF. Increased neurohormonal activity is now recognized as one of the major pathophysiological factors that contribute to the progression of CHF. Activation of neurohormonal mechanisms is only compensatory in the short term; chronic activation produces detrimental changes in the myocardkma, kidneys and peripheral vasculature. This article provides an overview of the key neurohormonal systems that are activated in CHF. (Eur Heart J Supplements 2002; 4 (Suppl D): D3-Dll) © 2002 The European Society of Cardiology

Introduction

perpetuating process that remains poorly understood. The limited number of agents proven to slow the development of CHF and reduce cardiovascular mortality (i.e. angiotensinconverting enzyme [ACE] inhibitors, beta-blockers and spironolactone) are all neurohormonal modulatorsE3J. These findings have led to the neurohormonal hypothesis of the progression of heart failure[4,5]. According to that hypothesis, neurohormonal activation in CHF is initially a beneficial and adaptive response. Eventually, however, excessive production of neurohormones becomes realadaptive, leading to progression of heart failure through a variety of mechanisms, including myocardial fibrosis with continuous LV remodelling, and necrotic and apoptotic myocyte death.

Chronic heart failure (CHF) was originally considered to be a haemodynamic disorder, and early treatment strategies therefore focused on correcting the haemodynamic derangements of the disease. Although these interventions often improved the haemodynamic status of the patients, they nevertheless adversely affected long-term outcome[a,2]. These findings raised questions regarding the validity of the haemodynamic explanation for CHF, suggesting that alternative mechanisms must play a primary role in the progression of the disease. Whenever the heart is damaged and cardiac output begins to fall, a number of neurohormones are activated, to restore circulatory homeostasis. Once established, however, left ventricular (LV) dysfunction progresses relentlessly to symptomatic heart failure, with high mortality[3]. Progression is related to ventricular remodelling, a self-

Correspondence:Professor Roberto Ferrari, Cattedra di Cardiologia, Universita' di Ferrara, H. S. Anna, Unit~ Operativa di CardiologiaUTIC, C.rso Giovecca 203, 44100 Ferrara, Italy. 1520-765X/02/0D0003 + 09 $35.00/0

Key Words: Chronic heart failure, left ventricular dysfunction, neurohormones, ventricular remodelling.

Neurohormonal activation in chronic heart failure Two sets of neurohormones, with opposing effects, are activated in CHF: the vasoconstrictor hormones (which are also antinatriuretic and antidiuretic, and have growth© 2002 The European Society of Cardiology

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During the past 50 years there have been vast improvements in the treatment of chronic heart failure (CHF). CHF was initially considered to be a cardio-renal problem - an acute disorder leading to volume expansion and oedema. Diuretics and digitalis were the only available treatments. Subsequently, CHF was considered to be the result of both myocardial dysfunction and increased tone in the pulmonary and peripheral circulations. The presence of peripheral vasoconstriction suggested that circulatory failure was an important component of the disease, and vasodilators were added to therapy. In the more recent past, experimental and clinical studies have demonstrated that CHF is also characterized by increased neurohormonal activation. This has led to the use of angiotensin-converting enzyme inhibitors, beta-blockers and

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Increased sympathetic activity as a prognostic tool

The mechanisms that are responsible for sympathetic activation in CHF are not entirely clear. Reduced clearance of noradrenaline due to low cardiac output probably contributes to its high circulating levels. However, most of the increase in plasma noradrenaline is due to excessive secretion. The stimulus for this is an early and sustained attenuation of cardiac and arterial baroreceptor control of sympathetic nerve activity, caused by a decrease in baroreceptor afferent discharge as a result of arterial 'underfilling'j10]. When CHF is established, increased peripheral chemoreceptor sensitivity and augmented muscle mechanoreceptor discharge may further modulate sympathetic activity[17].

Simple indices of sympathetic-parasympathetic balance, such as heart rate, are often used in the risk stratification of patients with CHF. Recently, however, more complex indices of autonomic nervous system dysfunction have been employed, particularly heart rate variability and baroreflex sensitivity. Frequency domain measures of heart rate variability have been proven to add valuable prognostic information for risk stratification after myocardial infarction[ 241 and in the identification of high-risk subgroups of CHF patients[9]. In addition, a large multicentre prospective study involving more than 1000 patients - the Automatic Tone and Reflexes After Myocardial Infarction (ATRAMI) study[25J - was conducted using baroreflex sensitivity as a prognostic index in post-myocardial infarction patients. Both heart rate variability and baroreflex sensitivity were found to be independent risk factors for mortality, emphasizing the clinical usefulness of autonomic markers. Apart from the direct indices of autonomic fimction mentioned above, plasma catecholamines (particularly noradrenaline) are the predictors of severity and outcome most widely and specifically studied. This approach goes back to 1984, when Cohn et al.[26~ identified plasma noradrenaline as a guide to prognosis in patients with CHF. In that original study, a single resting venous blood noradrenaline measurement appeared to be a more powerful prognostic predictor than other commonly measured indices of cardiac performance. This concept was verified in population-based studies, such as V-HeFT IIf271, in which high plasma noradrenaline had a significant independent impact on mortality, suggesting that measurements of cardiac dysfunction and exercise tolerance alone are insufficient to quantify the severity of the disease. A similar impact of plasma noradrenaline on mortality has been found in other large-scale trials[l°], although those findings need to be treated with some caution.

The role of excessive sympathetic activation in the progression of chronic heart failure Although the degree ofneurohormonal activation appears to be related to the severity of CHF, there is limited data demonstrating an increase in neurohormones with progression. In the canine model of pacing-induced heart failure, plasma noradrenaline (and other neurohormones) increase progressively as LV dysfimction worsens and cardiac output falls[18]. The increase in noradrenaline in this model occurs long before activation of the RAAS, at a stage comparable to asymptomatic LV dysfunction in humans[19]. Although these animal experiments suggest that progression of CHF is associated with a worsening neurohormonal profile, there is insufficient human data to draw similar conclusions. In fact, very few studies have reported sequential measurements ofneurohormones in patients with CHF. In one uncontrolled study of 22 patients receiving digoxin, diuretics and vasodilators[2°J, a progressive increase in plasma noradrenaline was reported over a 2-year follow-up. In a Studies of Left Ventricular Dysfunction (SOLVD) substudy[211, no significant change was seen in plasma noradrenaline or other hormones during a 1-year follow-up in patients with asymptomatic LV dysfunction or symptomatic heart failure. However, only patients who completed the 1-year follow-up were included in the study. Patients who died, and who might have had more significant changes in neurohormones, were excluded from the analysis. In addition, in the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) If221 no significant change was seen in neuroendocrine response in 126 patients receiving placebo who were followed up for 6 weeks. In the Veterans Administration Heart Failure Trial (V-HeFT) II[23], despite an increase in ejection fraction in both the enalapril and hydralazine-isosorbide dinitrate groups, levels of noradrenaline increased in both groups. This increase in noradrenaline did not appear to be correlated with the change in ejection fraction, suggesting that there was no relationship between progression or regression of LV dysfunction and changes in neurohormone levels in V-HeFT II.

Therapeutic implications of increased sympathetic activity Although beta-adrenergic blockers were historically considered contraindicated in CHF, they have now emerged as the most promising new form of therapy. Their use in heart failure dates back to the Scandinavian experience reported during the 1970s[281. Although there has always been concern that adding negative inotropic agents to the failing heart might exacerbate the clinical syndrome, new data from clinical trials have proved the benefit of betablockade in CHF[ 29~ 1]. In all of those studies, beta-blockers were administered in conjunction with an ACE inhibitor and diuretics. Blockade of sympathetic activity consistently improved prognosis and LV function, and reduced hospitalization and remodelling, providing clinical benefits over and above those achieved on standard therapy alone. Eur Heart J Supplements,Vol. 4 (Suppl D) April 2002

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What is the mechanism for excessive sympathetic activation ?

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Additional strategies designed to block the sympathetic nervous system are now emerging. Drugs that inhibit tyrosine hydroxylase, an enzyme step in the synthesis of norepinephrine, are currently under investigation, although it is unclear whether such agents will have any advantage over conventional beta-blockers.

The renin-angiotensin-aldosterone system

What is the role of increased activity of the RAAS in chronic heart failure? The initial beneficial effects of RAAS activation in CHF (preservation of glomerular filtration rate and support of blood pressure) may become deleterious if excessive and Eur Heart J Supplements,Vol. 4 (Suppl D) April 2002

What is the mechanism for increased RAAS activity in chronic heart failure? In normal individuals the RAAS is not activated and does not play a significant physiological role. However, in states of low cardiac output volume and salt depletion, during hypotension and in CHF, the RAAS is activated and exerts its vasoconstrictor and salt- and water-retaining effects. The increase in renin release from the juxtaglomerular ceils depends on changes in cardiac output that threaten renal blood flow and arterial perfusion pressure[351. In addition, changes in the sodium ion concentration in the region of the macula densa affect the rate of renin release. The responsiveness of the system is greatly increased by adrenergic stimuli, which act by enhancing the threshold of renin release[35].

What is the prognostic role of increased RAAS activity? ACE inhibitors increase renin plasma activity and reduce angiotensin II and aldosterone levels. Their widespread use in clinical practice limits the use of RAAS activation for prognostic purposes. A reduction in plasma aldosterone levels during therapy with ACE inhibitors is associated with a favourable impact on survival[36]. However, it is unclear whether ACE inhibitors actually normalize plasma aldosterone levels in patients with CHF. In patients with heart failure, ACE inhibitor doses are often constrained by the development of hypotension, and it is uncertain whether the reduction in plasma aldosterone induced by ACE inhibitors can be sustained. In hypertension, higher doses of ACE inhibitors are used, and full suppression of angiotensin II is more likely. An increase in aldosterone

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The importance of the RAAS in CHF has been known for nearly 50 years. Renin, an enzyme that is released from juxtaglomemlar cells of the kidney, cleaves the alpha-2globulin angiotensinogen produced in the liver, to form the inactive peptide angiotensin I. ACE, which is widely expressed, converts angiotensin I to angiotensin II. Renin is released in response to a number of stimuli that are commonly observed in CHF (reduced renal perfusion pressure, increased renal sympathetic activity, decreased delivery of sodium to the macula densa, and diuretic use). Angiotensin II, the active product of renin activity, is a potent vasoconstrictor. In addition, it augments the pre-synaptic release ofnoradrenaline and stimulates the release of aldosterone, which promotes salt and water retention by the kidney. Angiotensin II also has direct effects on the kidney. It constricts the efferent arterioles and helps to maintain the glomerular filtration rate; it also causes sodium reabsorption by a direct action on the renal tubules. Indirectly, through stimulation of thirst and vasopressin release, angiotensin II enhances water retention. The activity of the RAAS in the blood of CHF patients shows high variability. It usually increases in the early phase of CHF and normalizes in the later chronic phase. It becomes elevated in patients with untreated severe CHF[ 32] and in patients on diuretics[33]. The elegant studies reported by Watkins et a/.[341in dogs, with constriction of the inferior vena cava and pulmonary artery, help to explain the variability and lack of consistency in activity of the RAAS in CHF. In that model, plasma renin activity increased immediately after constriction but returned to normal as plasma volume and arterial blood pressure were restored to normal. Negative feedback control of RAAS through blood volume and arterial blood pressure, which occurs both in patients with CHF and in healthy control individuals, may also help to explain the variability in activation of RAAS that occurs in CHF. RAAS activity in a given individual would depend on the phase of fluid retention. Patients with salt and water retention would be expected to have higher RAAS activity than those who have reached a new steady state.

prolonged, because they may worsen the loading conditions of the heart. In addition, although RAAS activation initially preserves glomerular filtration rate, it eventually reduces it by causing vasoconstriction in the afferent and efferent arterioles. In the myocardium, RAAS activity and locally produced angiotensin II influence myocytes and fibroblasts, leading to myocyte hypertrophy, necrosis/apoptosis, and increased collagen turnover. In addition to mobilizing calcium from the intra-cellular stores, angiotensin II activates (via the cardiac angiotensin II type 1 receptors) an immediate-early gene response that plays an important role in the signalling cascade, finally leading to cardiac hypertrophy. Angiotensin II is also directly responsible for lesions that increase coronary artery permeability, allowing the diffusion of growth factors into the myocardial interstitium. Another action of angiotensin II is to stimulate aldosterone secretion. This not only has haemodynamic consequences but it also stimulates collagen synthesis by myocardial fibroblasts. Collectively, these adverse effects of RAAS activation may contribute to progressive ventricular remodelling and worsening heart failure[34].

Neurohormonal modulation in chronic heartfailure D7 Angiotensin II receptor blockers level is nonetheless observed after several months of ACE inhibitor administration[37L This aldosterone 'escape' hints that aldosterune and angiotensin II levels may become Angiotensin II receptor blocking drugs are now widely used elevated over time. It also raises the possibility that other to treat hypertension. Their role in CHF is less well defined, stimuli or alternative sites of aldosterone production but they are nevertheless increasingly used in this compensate for angiotensin II depression, so that ACE indication. These interesting agents are not a simple inhibition does not totally prevent secondary hyper- substitute for ACE inhibitors. The Losartan Heart Failure Survival Study (ELITE) I [45]found a significant reduction in aldosteronism in certain patients. An inverse linear relation exists between plasma renin sudden death among patients receiving losartan as activity and serum sodium concentration in patients with compared with those receiving captopril. In contrast, no CHF, and the renin-angiotensin system is activated in advantage was found for losartan in the ELITE II study[46], proportion to the clinical severity of the syndromeE381. which was powered to detect a difference. In fact, in ELITE Consequently, there is also a relationship - albeit very w e a k - II event rates were higher in patients receiving losartan than between plasma renin activity, serum sodium concentration in those receiving captopril (although the difference was not statistically significant). Inconclusive findings have also and survival in CHFI39]. been reported in the Valsartan in Heart Failure (Val-HeFT) trial[471. A clear role for angiotensin lI receptor blockers in CHF will probably be better defined when results of the What are the therapeutic advantages Valsartan In Acute Myocardial Infarction Trial (VALIANT) of counteracting the RAAS in become available. chronic heart failure?

Atrial and brain natriuretic peptides Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are members of a family of peptides that are synthesized primarily in atrial myocytes and released in response to atrial stretch. These peptides have natriuretic, vasodilator and antimitogenic properties. They also antagonize most endogenous vasoconstrictors by reducing sympathetic activity, and inhibiting renin and aldosterone release. The biological actions of ANP and BNP are achieved via a common receptor termed NPR-A, which is coupled to cyclic guanosine monophosphate. Levels of ANP and BNP are elevated early in CHF, along with sympathetic nervous system activity. This elevation precedes activation of the RAAS and occurs before symptoms of LV dysfunction appear[48-5o].

What is the role of increased ANP and BNP in chronic heart failure? ANP and BNP release is stimulated by stretching of the atrial tissue and by volume-loading of the circulation. Their increased concentration in the blood of patients with CHF therefore appears to be due to excessive release from overstretched atrial49]. Animal studies suggest that an early increase in ANP is responsible for the maintenance of sodium balance and inhibition of RAAS, in proportion to the rise in atrial pressure and severity of LV dysfunction[51J. This ANP elevation in turn inhibits the release of noradrenaline from nerve terminals, as well as the vasoconstrictor action of noradrenaline on systemic vessels. ANP also suppresses renin formation and counteracts the systemic vasoconstrictor action of angiotensin II, as well as its ability to stimulate thirst and aldosterone secretion. All of these mechanisms act together to lower systemic vascular Eur Heart J Supplements, Vol. 4 (Suppl D) April 2002

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ACE inhibitors have emerged as a treatment of choice for patients with CHF. There is now no doubt that they are highly beneficial in patients with New York Heart Association functional class I-IV heart failure. Virtually all patients with LV dysfunction and heart failure should be treated with an ACE inhibitor unless there is an obvious contraindication, such as shock, hyperkalaemia, or a rapidly rising serum creatinine. There appears to be a trend for patients to be under-dosed with ACE inhibitors[40L Most experts now recommend that these agents be titrated to the doses used in the large clinical trials, although this concept has been challenged[411. Despite extensive investigations conducted during the past two decades, the precise mechanisms whereby ACE inhibitors benefit patients with CHF are incompletely understood[42,43]. There are emerging data to suggest that prolonged inhibition of the RAAS does not occur with ACE inhibitors, and it is likely that there is an 'escape' phenomenon, despite persistent therapeutic efficacy. It is believed that that changes in tissue bradykinin associated with ACE inhibitor use may be relevant to their long-term pharmacological action, but this has not been conclusively demonstrated. The benefit of ACE inhibitors is clearly not simply a matter of after-load reduction, because there are numerous agents that reduce peripheral vascular resistance but do not have the benefits of ACE inhibitors. It may be that the antiadrenergic properties of ACE inhibitors, although relatively modest, are an important adjunctive mechanism. In both asymptomatic and symptomatic patients, ACE inhibitors favourably influence several parameters of remodelling (e.g. ejection fraction and LV end-systolic and end-diastolic volumes). The demonstration that the addition of low-dose spironolactone to standard CHF therapy improves prognosis dramatically[44] further underlines the role of aldosterone in CHF. It also suggests that the escape phenomenon is clinically relevant and that complete suppression of the RAAS with ACE inhibitors alone is difficult.

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resistance and increase sodium excretion, thereby unloading the heart and reducing its energy consumption[491. However, in severe heart failure, despite greatly increased ANP and BNP, natriuretic and vasodilator responses to these peptides are attenuated. This phenomenon may contribute to the salt and water retention, and systemic and renal vasoconstriction that are observed in severe heart failure. The mechanisms responsible for the attenuated response are unclear. A number of factors may be involved, including decreased renal blood flow, increased renal sympathetic activity, receptor downregulation, and enhanced enzymatic degradation of the peptides. In addition, ANP and BNP may exert an antiremodelling action via their antimitogenie effects, but this has not been fully elucidated.

What is" the prognostic role of increased ANP and BNP?

Is there a therapeutic role for ANP and BNP in chronic heart failure? Efforts to use natriuretic peptides as therapeutic agents in CHF have been disappointing[S°,56]. However, inhibition of neutral endopeptidase, the enzyme that degrades endogenous natriuretic peptides, potentiates the effects of the endogenous peptide. Drugs that are designed to block neutral endopeptidase have been the subject of experimental and clinical investigations[~T]. These drugs appear to increase plasma levels of ANP and, in principle, should improve renal blood flow and diuresis, and increase Eur Heart J Supplements,Vol. 4 (Suppl D) April 2002

Other hormones that are activated in chronic heart failure Arginine vasopressin Arginine vasopressin (AVP) is another vasoconstrictor and water-retaining hormone with mitogenic properties that may be potentially harmful in CHF. However, relatively little is known regarding its role in CHF. AVP is increased in some but not all patients with CHF[21,32,58]. Under normal conditions, osmoreceptors are the primary determinants of AVP release. In CHF, however, non-osmotic control of AVP release becomes more important. The important nonosmotic stimuli emanate from low- and high-pressure baroreceptors, angiotensin II, ANP and sympathetic activation. In addition, central dopaminergic and prostaglandin-related stimuli also operate. Some non-osmotic stimuli are abnormal in CHF. Therefore, despite the hypo-osmolarity and hyponatraemia that often occur in severe CHF (and which should suppress AVP), levels remain inappropriately elevated. AVP acts on vascular smooth muscle vasopressin-1 receptors to cause vasoconstriction, and on vasopressin-2 receptors in distal tubules and collecting ducts to enhance reabsorption of water. AVP probably contributes to vasoconstriction and fluid retention in CHF. Infusion of a specific vasopressin-1 receptor antagonist improves haemodynamics. High levels of AVP may also contribute to dilutional hyponatraemia in severe heart failure, a feature that indicates poor prognosis. Studies with specific AVP antagonists are required to establish whether inhibition of this system is useful.

Endothelins Endothelins belong to a family of potent vasoconstrictors that are released in CHF[581. They promote peripheral vasoconstriction by interacting with specific endothelin receptors, which are also found in the heart, kidney, adrenal gland and brain. Endothelin release therefore adds to afterload stress in heart failure. Endothelin-1 also has important mitogenic effects, including both myocyte hypertrophy and proliferation of the interstitial cardiac matrix. It also induces a number of hypertrophic features in neonatal cardiomyocytes. In adult cardiomyocytes, endothelin-1 stimulates phosphoinositide hydrolysis and nuclear transcriptional events. It therefore plays a role in growth regulation, and consequently in the progressive LV remodelling that characterizes CHF. Interestingly, in one study[591 endothelin-1 was found to be an independent predictor of mortality in CHF patients,

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Measurement of ANP/BNP is emerging as an important non-invasive marker of LV dysfunction and as a population screening tool[51]. In a substudy of the Survival and Ventricular Enlargement (SAVE) trial[521, ANP was a powerful predictor of cardiovascular mortality and of the development of CHF. In patients with CHF, BNP was an independent predictor of mortality and was superior to ANP[531. In an elderly population, BNP was also an independent predictor of mortality[54]. Natriuretic peptides are elevated in the absence of clinical signs and symptoms in patients with LV dysfunction, especially systolic LV dysfunction. This raises the possibility that they might also be useful in identifying patients with important but asymptomatic LV dysfunction who would benefit from appropriate investigation and treatment[511. The sensitivity and specificity of BNP renders it a very acceptable screening test for the general population, especially when applied to patients who are at high risk for LV dysfimction, such as those with coronary heart disease, hypertension, diabetes, or other vascular diseases. In this scenario, the positive predictive accuracy of BNP is relatively low but the negative predictive accuracy is 98%[55?. Thus, BNP could be used to rule out patients who are unlikely to have LV dysfunction; the remainder would then receive further investigation (usually echocardiography).

vasodilatation. They should also oppose remodelling. Because angiotensin II attenuates the effects of ANP, coinhibiting neutral endopeptidase and ACE enzymes in CI-IF may be an exciting therapeutic possibility.

Neurohormonal modulation in chronic heart failure

and to be a better predictor of mortality than ANP or noradrenaline. Another study[601 also found that endothelin- 1 predicted mortality, whereas ANR aldosterone and renin had no additional prognostic value. Those studies are small and the comparative data with respect to other neuroendocrine markers are by no means conclusive. Should these data be confirmed in large prospective studies, however, then the development of screening assays for endothelin would be justified. Animal studies have suggested that the early introduction of endothelin receptor blockers following experimental acute myocardial infarction is associated with a reduction in LV remodelling and an improvement in survival[61]. However, it is not known whether specific blockade of either the endothelin-1 or endothelin-2 receptor is more important than non-specific blockade of both receptors. Bosentan, a non-specific endothelin blocker, is associated with acute haemodynamic improvement, and is currently undergoing clinical investigation in patients with heart failure. Undoubtedly, more specific endothelin blockers, including endothelin-converting enzyme inhibitors, will emerge in the near future.

Growth hormone is secreted by the anterior pituitary, and its effects are mediated via activation of insulin-like growth factor-I. Levels of growth hormone are elevated in severe untreated low- and high-output heart failure, and in patients with cardiac cachexia[32,621. The exact role of growth hormone in CHF is not known. Treating CHF with human growth hormone has been shown to be beneficial in some but not all studies[631. Cortisol is another anterior pituitary hormone that is also elevated in various syndromes of CHF, possibly as part of a general stress response[321.

Calcitonin gene-related peptide Calcitonin gene-related peptide is a potent vasodilator that is released during heart failure[641. It is colocalized with substance P and vasoactive intestinal peptide in parasympathetic nerve endings in the heart, blood vessels and the nervous system. Short-term infusion of calcitonin generelated peptide in patients with CHF is associated with beneficial effects[651.

conditions with divergent haemodynamics, including chronic severe anaemia, chronic arteriovenous fistula, beriberi, Paget's disease and chronic obstructive pulmonary disease[66]. The common factor in all forms of heart failure, whether high- or low-output, appears to be a tendency toward low arterial blood pressure. Blood pressure is 'threatened' in low-output states because of low cardiac output, and in high-output states because of a decrease in systemic vascular resistance. However, the neurohormonal response of the body is similar in each. However, the neurohormonal response to low arterial pressure is not unique to low- or high-output syndromes of heart failure. It is also seen when blood pressure is reduced for other reasons; for example, during acute reduction in arterial pressure with nitroprusside[671 or during physical exercise[68], in which blood pressure is threatened by marked vasodilatation in exercising muscles. These findings support the theory[51 that the neurohormonal response evoked during CHF is the same as that which evolved to support survival of the species under two important conditions: haemorrhage and physical exercise. Under these circumstances, a short-term threat to blood pressure evokes a baroreceptor-mediated increase in sympathetic activity that causes venoconstriction, tachycardia, stimulation of the myocardium and regional vasconstriction. When blood pressure is threatened by reduced cardiac output due to LV dysfunction, the body cannot distinguish whether the threat is from haemorrhage, exercise, or heart disease. It therefore uses the same programmed and stereotyped response to all of these threats. The effector mechanisms continue to operate as long as the threat persists. In CHF, however, cardiac output is chronically depressed and the neuroendocrine response therefore remains chronically activated. Armed with this information, the pharmaceutical industry has begun to develop numerous therapeutic agents designed to manipulate neuroendocrine, cytokine and enzyme responses. ACE inhibitors and beta-adrenergic blockers stand out as classic examples of how neuroendocrine modulators can emerge as important therapies. In the near future, more evidence will emerge regarding the potential clinical usefulness of other neuroendocrine and enzyme modulators. Strategies for the future may include new agents designed to block the sympathetic nervous system, the renin-angiotensin system, endothelin, and the numerous cytokines and enzyme systems that are known to be important in the genesis of CHF.

References Conclusion The neurohormonal responses described above are observed in patients with low-output CHF. However, an identical neurohormonal response with retention of salt and water also occurs in a number of conditions in which the heart itself is normal but cardiac output is abnormally high. This so-called 'high-output' heart failure is seen in a range of

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