REVIEW

Neurohormonal activation in canine degenerative mitral valve disease: implications on pathophysiology and treatment Neurohormonal systems play a critical role in canine degenerative mitral valve disease (DMVD). DMVD results in mitral regurgitation, which reduces forward cardiac output and increases intracardiac pressures. These changes trigger neurohormonal responses that ultimately result in maladaptive cardiac remodelling, congestion and heightened morbidity and mortality. Medical therapies such as ACE inhibitors and spironolactone derive their benefit by interrupting or suppressing these neurohormonal responses. Thus, knowledge of neurohormonal mechanisms can lead to a better understanding of how to treat DMVD. M. A. OYAMA Journal of Small Animal Practice (2009) 50 (Suppl. 1), 3–11 DOI: 10.1111/j.1748-5827.2009.00801.x Accepted: 19 June 2009

Conflicts of Interest: MAO has acted as a paid consultant to IDEXX Laboratories and has received funding for research referenced in this work.

Department of Clinical Studies-Philadelphia, School of Veterinary Medicine, University of Pennsylvania, 3900 Delancey St., Philadelphia, PA 19107, USA Journal of Small Animal Practice

JSAP801.indd 3

•

NEUROHORMONAL ACTIVATION DMVD decreases forward cardiac output and increases intracardiac hydrostatic pressure. These changes elicit the response of multiple neurohormonal systems, whose activation maintains adequate cardiac output, blood pressure and tissue perfusion. The preservation of blood flow and pressure is accomplished by increasing renal sodium and water retention and eliciting peripheral vasoconstriction. The sympathetic nervous system (SNS) and the renin-angiotensin-aldosterone system (RAAS) are two well-described systems that are central to these effects. Fluid retention and vasoconstriction are furthered by the activation of the arginine vasopressin (AVP) and endothelin-1 (ET-1) systems. The natriuretic peptide system provides an endogenous counterbalance to these effects by promoting diuresis and vasodilation; however, in dogs with advanced DMVD, the effects of the natriuretic peptides are overwhelmed and the balance of activity favours vasoconstriction and fluid retention, resulting in increased cardiac afterload, deleterious myocardial remodelling and congestive heart failure (Fig 1) (Ware and others 1990, Pedersen and others 1995, Marcondes and others 2006).

Vol 50 (Suppl. 1) • September 2009

•

All neurohormonal systems have developed in a similar manner. There is an “input” afferent arm that detects alterations in physiological parameters such as pressure, oxygen tension or sodium concentration, and an “output” efferent arm that uses various neurohormonal molecules and targets receptors to modulate physiological responses (Table 1). The presence or absence of these receptors on different tissue types confers specificity to the system. Thus, actions can be targeted to myocardial cells, vascular smooth muscle or specific portions of the nephron. A system’s time course of activation is also important. Theoretically, therapy that disrupts these systems should be prescribed at the exact time point they become maladaptive. If therapy is prescribed before this point, it may be ineffective, incur financial waste and put the patient at risk for adverse side effects without hope of counterbalancing benefit. The remainder of this review will discuss the characteristics of the most important neurohormonal systems, their time course of activation, and what ramifications these characteristics have on deciding when and how to treat DMVD.

SYMPATHETIC NERVOUS SYSTEM The input arm of the SNS consists of pressure and chemical receptors within the central nervous system, carotid sinus, aortic arch, renal afferent arteries and heart. Reduced cardiac output and arterial hypotension offloads pressure receptors, resulting in a centrally mediated decrease in vagal tone and increase in sympathetic tone. Central and peripheral chemoreceptors respond to changes in lactic acid and oxygen and carbon dioxide tension. Hypercapnia, hypoxia and acidosis result in heightened sympathetic tone. When stimulated, SNS efferent activity is achieved through increased firing of

© 2009 British Small Animal Veterinary Association

3

14/8/09 8:54:36 AM

M. A. Oyama

Table 1. Major cardiovascular effects of various neurohormonal systems System

Input sensors

Output molecules

Target organs

Effect

Sympathetic nervous system

Baroreceptors and chemoreceptors*

Norepinephrine and epinephrine

Vascular smooth muscle Heart

Vasoconstriction Tachycardia Increased contractility

Renin-angiotensin-aldosterone system

Baroreceptors and chemoreceptors†

Angiotensin II

Vascular smooth muscle Heart Kidney Adrenal gland Central nervous system

Vasoconstriction Hypertrophy Sodium retention Aldosterone release Increased thirst

Aldosterone

Vascular smooth muscle Heart Kidney

Hypertrophy Hypertrophy, fibrosis Sodium retention

Natriuretic peptide system

Myocardial stretch

Atrial natriuretic peptide and B-type natriuretic peptide

Kidney Vascular smooth muscle Heart

Natriuresis, diuresis Vasodilation Antifibrotic

Arginine vasopressin system

Osmoreceptors Baroreceptors

Arginine vasopressin

Vascular smooth muscle Collecting duct

Vasoconstriction Water reabsorption

Endothelin-1

Endothelial cells

Endothelin-1

Vascular smooth muscle Heart

Vasoconstriction (ET-A) Vasodilation (ET-B) Increased contractility

*Central nervous system, carotid sinus, aortic arch, renal afferent arteries and heart. † Juxtaglomerular cells and macula densa.

sympathetic nerve terminals and release of norepinephrine (NE), decreased NE reuptake, increased central NE turnover and increased adrenal medullary production of epinephrine. These effector molecules bind to adrenergic receptors primarily in the heart and vasculature. In the normal heart, the primary adrenergic receptor is the β1 receptor. Binding of NE triggers a cascade of secondary messengers including cyclic adenosine monophosphate and protein kinases. Protein kinases phosphorylate a wide assortment of regulatory molecules within the myocardial cell that increases intracellular calcium,

resulting in increased force of contraction and increased heart rate. In peripheral smooth muscle, the primary adrenergic receptor is the α1 receptor. Binding of NE results in increased intracellular calcium that elicits vasoconstriction. Thus, increased SNS activity at the level of the heart and vasculature supports cardiac output and blood pressure, and the classic “fight or flight” role of the SNS is fulfilled. In the setting of heart disease, where cardiac injury is chronic and progressive, elevation of SNS activity is persistent and maladaptive. Chronically elevated SNS tone contributes to acceleration of disease

FIG 1. Neurohormonal pathophysiology of heart failure. Cardiac injury results in reduced cardiac output and arterial blood pressure, which activates maladaptive neurohormonal systems. These systems provide temporary haemodynamic support, but are associated with vasoconstriction, abnormal myocardial energetics, myocyte death and myocardial remodelling, which further injure the heart

4

JSAP801.indd 4

Journal of Small Animal Practice

•

through multiple processes, including myocyte hypertrophy, persistent tachycardia, increased myocardial oxygen demand, increased afterload, receptor downregulation, inefficient energy production and loss of myocytes through apoptosis and necrosis (Opie 2002). Thus, the harmful effects of long-term SNS activation outweigh the short-term beneficial effects, and suppression of SNS activity is a cornerstone of successful medical therapy in human beings with heart failure. In both human beings (Davila and others 2005) and dogs with experimental mitral regurgitation (Hankes and others 2006), SNS activity is increased relatively early in disease, first locally at the level of the heart and kidneys, and then in a more generalised systemic manner as disease progresses. This early local activity is mediated by NE release from SNS nerve endings within the heart and increases NE concentrations in the myocardial interstitial fluid and coronary sinus blood in dogs with experimentally produced mitral regurgitation (Farrell and others 2001, Hankes and others 2006). As disease progresses, local NE spills over into the general circulation, resulting in elevated plasma NE concentration. In dogs with DMVD, circulating NE levels tend to parallel the development of heart enlargement and are consistently elevated once congestive heart failure is present (Ware and others 1990,

Vol 50 (Suppl. 1) • September 2009

•

© 2009 British Small Animal Veterinary Association

14/8/09 8:54:37 AM

Neurohormonal activation in DMVD

FIG 2. M-mode echocardiogram of the left ventricle (LV) from a dog with advanced DMVD and mitral regurgitation. Note the pronounced excursions of the interventricular septum (white arrow) and left ventricular wall (red arrow), resulting in the appearance of increased ventricular contractility. This ventricular wall motion is typical in dogs with advanced mitral disease, yet experimental studies demonstrate that the contractility of individual myocardial fibres is reduced. The hyperdynamic ventricular wall motion is thought to be due to reduced ventricular afterload secondary to the large mitral valve leak

Uechi and others 2002, Santos and others 2006). In human beings, plasma NE and epinephrine levels are strongly correlated to survival (Cohn and others 1984, Kaye and others 1995). In virtually all instances of human systolic heart failure (reduced contractility) beta-blocker therapy is recommended (Hunt and others 2005). Why then are beta-blockers not routinely prescribed to dogs or people with DMVD? One of the primary indications for betablockade, namely reduced contractility, is difficult to demonstrate in dogs with DMVD. Routine echocardiographic measures of contractility such as fractional shortening or ejection fraction are confounded by the presence of moderate to severe mitral regurgitation. Both diastolic volume overload and low resistance to left ventricular ejection result in ventricular wall motion that appears “hyperdynamic”, and fractional shortening values are often normal or even exceed the reference range (Fig 2). Other echocardiographic indices such as absolute or indexed end-systolic diameter may be a better method to assess contractility in dogs with DMVD (Borgarelli and others 2007), but even these parameters are affected by low afterload. Thus, while routine echocardiographic study suggests normal or even enhanced contractility, closer clinical evaluation (Borgarelli and others 2007) as well as experiments that assess the individual myocardial cells indicates that contractility Journal of Small Animal Practice

JSAP801.indd 5

•

is significantly reduced (McGinley and others 2007). This mismatch of “measured” versus “true” contractility makes it difficult to know whether dogs with DMVD would benefit from either betablockade or positive inotropes. In human beings, DMVD is routinely corrected via surgical methods and large clinical studies of long-term beta-blockade are lacking. Two pilot studies in human beings with DMVD and normal indices of contractility suggest that beta-blockade reduces cardiac work and mortality (Stewart and others 2008, Varadarajan and others 2008). Interestingly, the combined positive inotrope-vasodilator pimobendan, which has been shown to improve survival in dogs with DMVD (Häggström and others 2008), has been associated with reduced plasma NE levels (Kanno and others 2007). In dogs with advanced DMVD, administration of beta-blockers can result in acute decompensation, hypotension and congestive heart failure. Thus, despite compelling evidence in both human beings and experimental models indicating that chronic SNS stimulation is harmful, specific guidelines regarding routine betablockade in dogs with DMVD are lacking until more clinical data are available. Renin-angiotensin-aldosterone system The input arm of the RAAS consists of the juxtaglomerular cells of the afferent renal

Vol 50 (Suppl. 1) • September 2009

•

arteriole and the macula densa cells of the distal convoluted tubule. Either decreased renal blood flow or renal tubular sodium chloride concentration elicits production of preprorenin from the juxtaglomerular cells. Preprorenin is quickly cleaved to prorenin and then to renin by a trypsin-like enzyme. Renin converts angiotensinogen that is produced by the liver into angiotensin I. Angiotensin I is then converted into angiotensin II (ATII) by angiotensin converting enzyme (ACE) as it passes through the pulmonary capillaries (Fig 3). The biological actions of ATII are contributory to the progression of heart disease and elevated ATII levels are predictive of cardiovascular death (Roig and others 2000). The output arm of the RAAS system involves two different ATII receptors, AT-R1 and AT-R2. The heart and peripheral vascular smooth muscle are rich in AT-R1 and binding increases contractility, vasoconstriction, hypertrophy, remodelling and myocardial fibrosis. AT-R1 are also present in the kidneys and activation promotes active sodium exchange within the proximal and distal convoluted tubules, vasoconstriction of renal blood vessels and passive retention of sodium within the loop of Henle. Centrally located AT-R1 mediate increased thirst while AT-R1 within the cortex of the adrenal gland stimulate aldosterone secretion. Thus, the net effect of ATII and AT-R1 binding is fluid retention, vasoconstriction and vascular and myocardial remodelling. The functions of AT-R2 are generally contrary to those of AT-R1, in that AT-R2 elicits vasodilation; however, selective stimulation of AT-R2 can also induce myocyte damage, hypertrophy and cell death (Henrion and others 2001). The RAAS is generally stimulated in dogs with congestive heart failure secondary to DMVD (Knowlen and others 1983, Sisson 2004); however, this is not uniform across all studies (Häggström and others 1997). In both human beings and dogs, the time point of systemic activation approximates the development of symptomatic disease; however due to differences in measurement techniques, breed, dietary sodium intake and concurrent medications, it is difficult to know exactly when during the course of disease the RAAS is activated. In human beings,

© 2009 British Small Animal Veterinary Association

5

14/8/09 8:54:38 AM

M. A. Oyama

Finally, alternate pathways of ATII production may be able to circumvent ACE. In dogs, this alternate system involves chymase and kallikrein (Dell’italia and others 1995, Sasaguri and others 1999, Fujii and others 2007). Tissue chymase converts angiotensin I to ATII, while kallikrein converts angiotensinogen directly to ATII. Thus, both ATII and aldosterone can be elevated in (human) patients despite the use of ACE inhibitors. Tang and others (2002) reported that 35 and 85 per cent of human beings receiving ACE inhibitors demonstrated elevated serum aldosterone and ATII concentrations, respectively. Due to this phenomenon of “aldosterone escape”, adjunctive therapy with specific aldosterone blockers, such as spironolactone, or specific AT-R1 blockers is attractive (Tang and Francis 2005).

NATRIURETIC PEPTIDES

FIG 3. Renin-angiotensin-aldosterone system. Low hydrostatic pressure or low intratubular sodium or chloride concentration triggers release of renin from the renal juxtaglomerular apparatus (JGA). Renin converts angiotensinogen to angiotensin I, which is then converted into angiotensin II (ATII) by ACE. ATII acts on angiotensin receptor type 1 (AT-R1) to cause increased contractility, vasoconstriction and cardiac hypertrophy and fibrosis. Binding of ATII to angiotensin receptor type-2 causes vasodilation and diuresis. ATII also elicits release of aldosterone from the adrenal gland, which promotes sodium retention and cardiac hypertrophy and fibrosis. Note that ATII can be produced by two non-ACE mediated pathways: chymase converts angiotensin I to ATII and kallikrein converts angiotensinogen directly into ATII; DCT distal convoluted tubule

RAAS activation is preceded by SNS activation (Francis 1990); however, data specific to human beings with primary mitral valve disease are lacking. In dogs with mild asymptomatic DMVD, renin, angiotensin I, ATII and aldosterone are either not elevated (Häggström and others 1997, Fujii and others 2007) or variably elevated (Pedersen and others 1995, 1999, Pedersen 1996, Rush and others 2000) in comparison with normal dogs. ACE inhibition improves survival in dogs with symptomatic DMVD (COVE Study Group 1995, Ettinger and others 1998) but does not appear to substantially reduce risk for congestive heart failure when used in dogs with asymptomatic disease (Kvart and others 2002, Atkins and others 2007). These findings are most consistent with a relatively late time course of systemic RAAS activation. 6

JSAP801.indd 6

Interestingly, components of the RAAS are found in many tissues including the heart and kidney, and local tissue RAAS may be of importance. Fujii and others (2007) reported that myocardial ACE activity was increased in dogs with mild experimental mitral regurgitation while circulating renin, angiotensin I, ATII and aldosterone were normal. Thus, similar to the SNS, local RAAS activity may be important in the early stages of DMVD prompting consideration of ACE inhibitors with high tissue-ACE specificity (as opposed to systemic ACE); however, it should be noted that overzealous ACE inhibition may be detrimental. In dogs with experimental mitral regurgitation, aggressive ACE inhibition suppresses myocardial collagen formation and leads to progressive cardiac chamber enlargement (Dell’italia and others 1997).

Journal of Small Animal Practice

•

The natriuretic peptide system consists of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and C-type natriuretic peptide (CNP). In human beings, cardiac production and release of ANP and BNP are primarily mediated through stretch of the myocardial tissue (Magga and others 1998), although other stimuli such as SNS or RAAS activity (Wiese and others 2000, Sakata and others 2009), ET1 (Rademaker and others 2004), ischaemia (Goetze and others 2003) and inflammation (Vila and others 2008) can also trigger release. Both peptides are released in the form of a pro-hormone which is rapidly cleaved to an inactive N-terminal product (NT-proANP, NT-proBNP) and a biologically active C-terminal end (C-ANP, CBNP). C-ANP and C-BNP primarily bind to natriuretic peptide receptor-A (NPRA), which is located in the heart, kidney, vascular smooth muscle, brain and adrenal glands. Binding induces cyclic guanine monophosphate production, which causes vasodilation, increased glomerular blood flow and filtration rate, reduced sodium uptake, natriuresis and diuresis. In this manner, the natriuretic peptide system acts as the heart’s “volume sensor”, such that an increase in blood volume triggers natriuresis and diuresis. Both C-ANP and C-BNP have relatively short half-lives and are best

Vol 50 (Suppl. 1) • September 2009

•

© 2009 British Small Animal Veterinary Association

14/8/09 8:54:41 AM

Neurohormonal activation in DMVD

suited for short-term modulation of volume. Both molecules are degraded by circulating endopeptidases and both bind to NPR-C, which internalises and hydrolyses the molecule. NPR-C is distributed mainly in areas of high blood flow such as the kidney, adrenal gland, pulmonary tissue, heart and brain. Both ANP and BNP are foetal genes that are predominantly expressed at birth, and then reinduced in instances of disease. Both peptides are produced by atrial tissue; however, in instances of disease, ventricular BNP production is increased. CNP is predominantly produced in the brain and vascular tissues where it is thought to act in a paracrine manner to cause vasodilation. ANP and BNP are increased in dogs with heart failure and help reduce diastolic volume and improve diastolic function (Häggström and others 1994, 1997, 2000, Asano and others 1999, Lainchbury and others 2000, Boswood and others 2003, 2008, Greco and others 2003, MacDonald and others 2003, DeFrancesco and others 2007, Oyama and others 2008, Tarnow and others 2009). Initial veterinary studies used assays to detect C-ANP and C-BNP, while more recent studies

predominantly measure NT-proANP and NT-proBNP. The greater stability and longer half-life of these N-terminal fragments is better suited to ELISA-based immunoassay techniques. In human beings, natriuretic peptide assays help diagnose congestive heart failure, differentiate cause of respiratory distress and provide prognosis (Swedberg and others 2005, Maisel and others 2008). In dogs with DMVD, the natriuretic peptides are correlated to heart size and clinical signs (Häggström and others 1994, 2000, MacDonald and others 2003, Oyama and others 2008, Tarnow and others 2009). The time course of activation generally mirrors the development of cardiac enlargement. In dogs with mild disease, ANP (Asano and others 1999) and BNP (MacDonald and others 2003, Oyama and others 2008) are only variably elevated. The sensitivity of NTproANP may be greater than NT-proBNP for detection of mild disease.(Asano and others 1999, Häggström and others 2000) As disease progresses, ANP and BNP tend to increase, and are significantly elevated before the onset of congestive heart failure (Fig 4) (Tarnow and others 2009). In human beings with valve disease, ANP and

FIG 4. Circulating concentrations of N-terminal B-type natriuretic peptide (NT-proBNP) and left atrial to aortic root ratio (LA:Ao) in dogs with DMVD. Note the progressive increase in both NT-proBNP and left atrial size as disease progresses from minimal disease to overt congestive heart failure. Interestingly, dogs with severe yet asymptomatic disease have elevated NT-proBNP as compared with dogs with minimal or mild disease, and this might forewarn of the transition to congestive heart failure. Graph adapted from Tarnow and others (2009) Journal of Small Animal Practice

JSAP801.indd 7

•

Vol 50 (Suppl. 1) • September 2009

•

BNP typically, but not consistently, correlate to severity of regurgitation, heart size and symptoms (Sutton and others 2003, Mayer and others 2004, Detaint and others 2005, Ray 2006). In one study (Detaint and others 2005), BNP independently predicted mortality over a 4-year followup period. Greco and others (2003) reported that in a cohort of 23 dogs, C-ANP greater than 95 pg/ml was associated with shorter median survival, and MacDonald and others (2003) reported that in a cohort of 25 dogs with DMVD, for every 10 pg/ml increase in C-BNP, mortality over 4 months’ time increased by 44 per cent. The practical considerations of natriuretic peptide activation involve using natriuretic peptides either as therapeutic agents or as markers of disease severity and outcome. In human beings with acute heart failure, infusion of BNP is associated with both haemodynamic and symptomatic improvement. Most (Publication Committee for the VMAC Investigators 2002, Keating and Goa 2003, Peacock and others 2005, Sakr and others 2008) but not all (Miller and others 2008) studies demonstrate that addition of BNP infusion to routine care reduces length of hospital stay and incidence of future hospitalisation. The value of BNP infusion in dogs with DMVD is unknown. In human beings (Silver and others 2004, Arnold and others 2007) and dogs (Boswood and others 2008), NT-proANP and NT-proBNP have been used to assist in diagnosis of heart disease, staging of disease severity and discrimination between cardiac and non-cardiac causes of dyspnea (Fine and others 2008, Oyama and others 2008). In human beings, treatment decisions based on natriuretic peptide levels yielded better outcomes (Troughton and others 2000, Jourdain and others 2007); however, this finding has recently been called into question (Pfisterer and others 2009). The use of natriuretic peptide levels to predict onset of congestive heart failure, guide treatment and predict outcome in dogs with DMVD are intriguing applications that await further study.

ARGININE VASOPRESSIN The input arm of the AVP system involves both osmotic and non-osmotic stimuli.

© 2009 British Small Animal Veterinary Association

7

14/8/09 8:54:42 AM

M. A. Oyama

Osmoreceptors in the portal veins and hypothalamus monitor plasma osmolality and increase central AVP release from the posterior pituitary. Non-osmotic regulation via baroreceptors in the heart, great vessels and carotid sinus also mediates AVP release. The output arm of AVP involves two main peripheral receptors: V1a receptors are present on vascular smooth muscle and elicit vasoconstriction and V2 receptors are responsible for the antidiuretic properties of this hormone. They are located in the renal collecting duct and activate aquaporin-2 channels, resulting in water reabsorption. In cases of severe disease, prolific AVP release and free water resorption dilutes serum sodium concentration, and this dilutional hyponatraemia is a poor prognostic sign in both dogs (Brady and others 2004) and human beings (Gheorghiade and others 2007). AVP concentrations generally increase in human beings as cardiac disease progresses (Francis and others 1990). In human beings, the role of AVP antagonism in long-term management of heart failure is questionable. V2 or combined V1a and V2 receptor antagonists increase free water excretion and increase serum sodium concentrations, but do not delay the progression of heart failure or reduce mortality (Farmakis and others 2008, Schweiger and Zdanowicz 2008).

ENDOTHELIN-1 ET-1 is produced by vascular endothelial cells in response to shear stress, hypoxia, ATII and AVP. ET-1 acts primarily at ET-A receptors on vascular smooth muscle, especially within the aorta, kidneys and heart, where it increases intracellular calcium and elicits profound and sustained vasoconstriction. ET-A receptors are also found on myocardial cells where activation increases contractility. ET-1 can also bind to ET-B receptors that are located on vascular endothelium, and through formation of nitric oxide relaxes adjacent smooth muscle cells. ET-B receptors that are located directly on the vascular smooth muscle, however, elicit vasoconstriction when simulated. Thus, ET-1 contributes to overall vascular tone through a complex arrangement of receptor types and 8

JSAP801.indd 8

locations. In human beings with heart disease, ET-1 levels are elevated and predictive of mortality (Pousset and others 1997, Van Beneden and others 2004). ET-1 is elevated in dogs with experimental heart failure (Ray and others 2008) as well as in dogs with DMVD or dilated cardiomyopathy (Prosek and others 2004, Tessier-Vetzel and others 2006). Dogs with mild disease have ET-1 levels similar to control, suggesting that the time course of ET-1 activation is relatively late in disease (Prosek and others 2004). In human beings, ET-1 is thought to contribute to a wide array of disease conditions including pulmonary hypertension, renal disease, insulin resistance, cancer and atherosclerosis (Barton and Yanagisawa 2008). Therapy that targets ET-1 has been disappointing. ET-A receptor blockade improves haemodynamics but does not reduce mortality in human beings (Tang and Francis 2005). A recent study involving a mixed ET-A and ET-B blocker was associated with early worsening followed by a trend towards improved symptoms at 6 months, but the study was prematurely discontinued due to suspected hepatic side effects (Anand and Florea 2008). The studies involving blockade of AVP and ET-1 present an interesting conundrum. Blockade of some neurohormonal pathways improves outcome while blockade of others fails to demonstrate improvement, and may actually be deleterious. Thus far, every agent that has proven beneficial in human beings (that is, beta-blockers, ACE inhibitors and aldosterone antagonists) elicit reverse cardiac remodelling; that is, they are associated with a reduction in heart size, a return to a more normal ventricular geometry and reduced cardiac hypertrophy and fibrosis (Anand and Florea 2008; Tang and Francis 2005). In veterinary medicine, where studies seeking to prove a drug’s survival benefit are often confounded by euthanasia, small patient populations and concurrent medications, using indices of reverse remodelling as surrogate endpoints may be justifiable.

and some are likely to emerge as important to the development and progression of heart disease as well as potential therapeutic targets. Cardiotrophin-1 (CT-1) is a member of the interleukin-6 superfamily and promotes myocardial hypertrophy. CT-1 is induced by myocardial stretch and its release has been shown to precede that of BNP, making it a potential marker for heart disease in human beings (Jougasaki and others 2003). Adrenomedullin is a member of the calcitonin gene-related peptide family and is found in the heart, adrenal gland and vasculature. The effects of adrenomedullin are mainly protective, that is antiapoptotic, vasodilatory, antifibrotic and diuretic (Yanagawa and Nagaya 2007). In human beings, adrenomedullin is increased in heart failure and predicts future cardiovascular events such as stroke and heart failure (Nishida and others 2008). In dogs with experimental heart failure, expression of adrenomedullin is also upregulated (Jougasaki and others 2001). Apelin is an endogenous positive inotrope and vasodilator produced by vascular endothelium and is speculated to counteract the activities of ATII (Chandrasekaran and others 2008). It is downregulated in heart failure and thought to contribute to loss of contractility (Japp and Newby 2008). Urotensin II is the most potent vasoconstrictor identified to date with potency 10 times that of ET-1. Interestingly, its effects on cardiac function can include both positive and negative inotropes and either vasoconstriction or vasodilation depending on the state of the vascular bed (Russell 2008). Urotensin II is elevated in human beings with heart failure (Richards and others 2002). Urocortin is a member of the corticotrophin releasing hormone family and has been shown to protect against ischaemia and reperfusion injury (Davidson and others 2009) as well as improve heart function in animal models of heart failure (Bale and others 2004).

CONCLUSIONS OTHER NEUROHORMONES In addition to those already discussed, many other neurohormonal systems exist,

Journal of Small Animal Practice

•

Activation of neurohormonal systems occurs in dogs with DMVD. Early changes consist of increased tissue activity of the SNS and possibly the RAAS, followed

Vol 50 (Suppl. 1) • September 2009

•

© 2009 British Small Animal Veterinary Association

14/8/09 8:54:42 AM

Neurohormonal activation in DMVD

by production of protective natriuretic peptides in an attempt to counterbalance systemic activation of both the SNS and RAAS as heart disease progresses to heart failure. Along with ET-1 and AVP, the SNS and RAAS overwhelm the natriuretic peptide system and signs of congestion develop. By reducing activity of the RAAS, ACE inhibitors improve outcome in dogs with symptomatic MVD, and it is hopeful that beta-adrenergic blockade will also prove to be beneficial. Specific aldosterone blocking agents such as spironolactone help mitigate the adverse effects of ATII and aldosterone made via nonACE pathways. Human studies involving ET-1 and AVP blockers have been disappointing, underscoring the limitations of “complete” neurohormonal blockade. Emerging neurohormonal systems may improve our understanding of the pathophysiology of heart failure and yield therapies that reduce disease progression and improve outcome. References ANAND, I. S. & FLOREA, V. G. (2008) Traditional and novel approaches to management of heart failure: successes and failures. Cardiology Clinics 26, 59-72 ARNOLD, J. M., HOWLETT, J. G., DORIAN, P., DUCHARME, A., GIANNETTI, N., HADDAD, H., HECKMAN, G. A., IGNASZEWSKI, A., ISAAC, D., JONG, P., LIU, P., MANN, E., MCKELVIE, R. S., MOE, G. W., PARKER, J. D., SVENDSEN, A. M., TSUYUKI, R. T., O’HALLORAN, K., ROSS, H. J., RAO, V., SEQUEIRA, E. J. & WHITE, M. (2007) Canadian Cardiovascular Society Consensus Conference recommendations on heart failure update 2007: prevention, management during intercurrent illness or acute decompensation, and use of biomarkers. Canadian Journal of Cardiology 23, 21-45 ASANO, K., MASUDA, K., OKUMURA, M., KADOSAWA, T. & FUJINAGA, T. (1999) Plasma atrial and brain natriuretic peptide levels in dogs with congestive heart failure. The Journal of Veterinary Medical Science 61, 523-529 ATKINS, C. E., KEENE, B. W., BROWN, W. A., COATS, J. R., CRAWFORD, M. A., DEFRANCESCO, T. C., EDWARDS, N. J., FOX, P. R., LEHMKUHL, L. B., LUETHY, M. W., MEURS, K. M., PETRIE, J. P., PIPERS, F. S., ROSENTHAL, S. L., SIDLEY, J. A. & STRAUS, J. H. (2007) Results of the veterinary enalapril trial to prove reduction in onset of heart failure in dogs chronically treated with enalapril alone for compensated, naturally occurring mitral valve insufficiency. Journal of the American Veterinary Medical Association 231, 1061-1069 BALE, T. L., HOSHIJIMA, M., GU, Y., DALTON, N., ANDERSON, K. R., LEE, K. F., RIVIER, J., CHIEN, K. R., VALE, W. W. & PETERSON, K. L. (2004) The cardiovascular physiologic actions of urocortin II: acute effects in murine heart failure. Proceedings of the National Academy of Sciences of the United States of America 101, 3697-3702 BARTON, M. & YANAGISAWA, M. (2008) Endothelin: 20 years from discovery to therapy. Canadian Journal of Physiology and Pharmacology 86, 485-498 BORGARELLI, M., TARDUCCI, A., ZANATTA, R. & HÄGGSTRÖM, J. (2007) Decreased systolic function and inadequate hypertrophy in large and small breed dogs

Journal of Small Animal Practice

JSAP801.indd 9

•

with chronic mitral valve insufficiency. Journal of Veterinary Internal Medicine 21, 61-67 BOSWOOD, A., ATTREE, S. & PAGE, K. (2003) Clinical validation of a proANP 31-67 fragment ELISA in the diagnosis of heart failure in the dog. The Journal of Small Animal Practice 44, 104-108 BOSWOOD, A., DUKES-MCEWAN, J., LOUREIRO, J., JAMES, R. A., MARTIN, M., STAFFORD-JOHNSON, M., SMITH, P., LITTLE, C. & ATTREE, S. (2008) The diagnostic accuracy of different natriuretic peptides in the investigation of canine cardiac disease. The Journal of Small Animal Practice 49, 26-32 BRADY, C. A., HUGHES, D. & DROBATZ, K. J. (2004) Association of hyponatremia and hyperglycemia with outcome in dogs with congestive heart failure. Journal of Veterinary Emergency and Critical Care 14, 177-182 CHANDRASEKARAN, B., DAR, O. & MCDONAGH, T. (2008) The role of apelin in cardiovascular function and heart failure. European Journal of Heart Failure 10, 725-732 COHN, J. N., LEVINE, T. B., OLIVARI, M. T., GARBERG, V., LURA, D., FRANCIS, G. S., SIMON, A. B. & RECTOR, T. (1984) Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. The New England Journal of Medicine 311, 819-823 COVE STUDY GROUP. (1995) Controlled clinical evaluation of enalapril in dogs with heart failure: results of the Cooperative Veterinary Enalapril Study Group. Journal of Veterinary Internal Medicine 9, 243-252 DAVIDSON, S. M., RYBKA, A. E. & TOWNSEND, P. A. (2009) The powerful cardioprotective effects of urocortin and the corticotropin releasing hormone (CRH) family. Biochemical Pharmacology 77, 141-150 DAVILA, D. F., NUNEZ, T. J., ODREMAN, R. & DE DAVILA, C. A. (2005) Mechanisms of neurohormonal activation in chronic congestive heart failure: pathophysiology and therapeutic implications. International Journal of Cardiology 101, 343-346 DEFRANCESCO, T. C., RUSH, J. E., ROZANSKI, E. A., HANSEN, B. D., KEENE, B. W., MOORE, D. T. & ATKINS, C. E. (2007) Prospective clinical evaluation of an ELISA B-type natriuretic peptide assay in the diagnosis of congestive heart failure in dogs presenting with cough or dyspnea. Journal of Veterinary Internal Medicine 21, 243-250 DELL’ITALIA, L. J., BALCELLS, E., MENG, Q. C., SU, X., SCHULTZ, D., BISHOP, S. P., MACHIDA, N., STRAETERKNOWLEN, I. M., HANKES, G. H., DILLON, R., CARTEE, R. E. & OPARIL, S. (1997) Volume-overload cardiac hypertrophy is unaffected by ACE inhibitor treatment in dogs. The American Journal of Physiology 273, H961-H970 DELL’ITALIA, L. J., MENG, Q. C., BALCELLS, E., STRAETERKNOWLEN, I. M., HANKES, G. H., DILLON, R., CARTEE, R. E., ORR, R., BISHOP, S. P. & OPARIL, S. (1995) Increased ACE and chymase-like activity in cardiac tissue of dogs with chronic mitral regurgitation. The American Journal of Physiology 269, H2065H2073 DETAINT, D., MESSIKA-ZEITOUN, D., AVIERINOS, J. F., SCOTT, C., CHEN, H., BURNETT JR., J. C. & ENRIQUEZ-SARANO, M. (2005) B-type natriuretic peptide in organic mitral regurgitation: determinants and impact on outcome. Circulation 111, 2391-2397 ETTINGER, S. J., BENITZ, A. M., ERICSSON, G. F., CIFELLI, S., JERNIGAN, A. D., LONGHOFER, S. L., TRIMBOLI, W. & HANSON, P. D. (1998) Effects of enalapril maleate on survival of dogs with naturally acquired heart failure. The Long-Term Investigation of Veterinary Enalapril (LIVE) Study Group. Journal of the American Veterinary Medical Association 213, 1573-1577 FARMAKIS, D., FILIPPATOS, G., KREMASTINOS, D. T. & GHEORGHIADE, M. (2008) Vasopressin and vasopressin antagonists in heart failure and hyponatremia. Current Heart Failure Reports 5, 91-96 FARRELL, D. M., WEI, C. C., TALLAJ, J., ARDELL, J. L., ARMOUR, J. A., HAGEMAN, G. R., BRADLEY, W. E. &

Vol 50 (Suppl. 1) • September 2009

•

DELL’ITALIA, L. J. (2001) Angiotensin II modulates catecholamine release into interstitial fluid of canine myocardium in vivo. American Journal of Physiology. Heart and Circulatory Physiology 281, H813-H822 FINE, D. M., DECLUE, A. E. & REINERO, C. R. (2008) Evaluation of circulating amino terminal-pro-Btype natriuretic peptide concentration in dogs with respiratory distress attributable to congestive heart failure or primary pulmonary disease. Journal of the American Veterinary Medical Association 232, 1674-1679 FRANCIS, G. S. (1990) Neuroendocrine activity in congestive heart failure. The American Journal of Cardiology 66, 33D-38D FRANCIS, G. S., BENEDICT, C., JOHNSTONE, D. E., KIRLIN, P. C., NICKLAS, J., LIANG, C. S., KUBO, S. H., RUDINTORETSKY, E. & YUSUF, S. (1990) Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. A substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 82, 1724-1729 FUJII, Y., ORITO, K., MUTO, M. & WAKAO, Y. (2007) Modulation of the tissue reninangiotensin-aldosterone system in dogs with chronic mild regurgitation through the mitral valve. American Journal of Veterinary Research 68, 1045-1050 GHEORGHIADE, M., ROSSI, J. S., COTTS, W., SHIN, D. D., HELLKAMP, A. S., PINA, I. L., FONAROW, G. C., DEMARCO, T., PAULY, D. F., ROGERS, J., DISALVO, T. G., BUTLER, J., HARE, J. M., FRANCIS, G. S., STOUGH, W. G. & O’CONNOR, C. M. (2007) Characterization and prognostic value of persistent hyponatremia in patients with severe heart failure in the ESCAPE Trial. Archives of Internal Medicine 167, 19982005 GOETZE, J. P., CHRISTOFFERSEN, C., PERKO, M., ARENDRUP, H., REHFELD, J. F., KASTRUP, J. & NIELSEN, L. B. (2003) Increased cardiac BNP expression associated with myocardial ischemia. The FASEB Journal 17, 1105-1107 GRECO, D. S., BILLER, B. & VAN LIEW, C. H. (2003) Measurement of plasma atrial natriuretic peptide as an indicator of prognosis in dogs with cardiac disease. The Canadian Veterinary Journal 44, 293-297 HÄGGSTRÖM, J., BOSWOOD, A., O’GRADY, M., JONS, O., SMITH, S., SWIFT, S., BORGARELLI, M., GAVAGHAN, B., KRESKEN, J. G., PATTESON, M., ABLAD, B., BUSSADORI, C. M., GLAUS, T., KOVACEVIC, A., RAPP, M., SANTILLI, R. A., TIDHOLM, A., ERIKSSON, A., BELANGER, M. C., DEINERT, M., LITTLE, C. J., KVART, C., FRENCH, A., RONN-LANDBO, M., WESS, G., EGGERTSDOTTIR, A. V., O’SULLIVAN, M. L., SCHNEIDER, M., LOMBARD, C. W., DUKES-MCEWAN, J., WILLIS, R., LOUVET, A. & DIFRUSCIA, R. (2008) Effect of pimobendan or benazepril hydrochloride on survival times in dogs with congestive heart failure caused by naturally occurring myxomatous mitral valve disease: the QUEST study. Journal of Veterinary Internal Medicine 22, 1124-1135 HÄGGSTRÖM, J., HANSSON, K., KARLBERG, B. E., KVART, C. & OLSSON, K. (1994) Plasma concentration of atrial natriuretic peptide in relation to severity of mitral regurgitation in Cavalier King Charles Spaniels. American Journal of Veterinary Research 55, 698703 HÄGGSTRÖM, J., HANSSON, K. & KVART C. (2000) Relationship between different natriuretic peptides and severity of naturally acquired mitral regurgitation in dogs with chronic myxomatous valve disease. Journal of Veterinary Cardiology 2, 7-16 HÄGGSTRÖM, J., HANSSON, K., KVART, C., KARLBERG, B. E., VUOLTEENAHO, O. & OLSSON, K. (1997) Effects of naturally acquired decompensated mitral valve regurgitation on the renin-angiotensin-aldosterone system and atrial natriuretic peptide concentration in dogs. American Journal of Veterinary Research 58, 77-82 HANKES, G. H., ARDELL, J. L., TALLAJ, J., WEI, C. C., ABAN, I., HOLLAND, M., RYNDERS, P., DILLON, R., CARDINAL, R., HOOVER, D. B., ARMOUR, J. A., HUSAIN, A. & DELL’ITALIA, L. J. (2006) Beta1-adrenoceptor blockade mitigates

© 2009 British Small Animal Veterinary Association

9

14/8/09 8:54:43 AM

M. A. Oyama

excessive norepinephrine release into cardiac interstitium in mitral regurgitation in dog. American Journal of Physiology. Heart and Circulatory Physiology 291, H147-H151 HENRION, D., KUBIS, N. & LEVY, B. I. (2001) Physiological and pathophysiological functions of the AT(2) subtype receptor of angiotensin II: from large arteries to the microcirculation. Hypertension 38, 1150-1157 HUNT, S. A., ABRAHAM, W. T., CHIN, M. H., FELDMAN, A. M., FRANCIS, G. S., GANIATS, T. G., JESSUP, M., KONSTAM, M. A., MANCINI, D. M., MICHL, K., OATES, J. A., RAHKO, P. S., SILVER, M. A., STEVENSON, L. W., YANCY, C. W., ANTMAN, E. M., SMITH JR., S. C., ADAMS, C. D., ANDERSON, J. L., FAXON, D. P., FUSTER, V., HALPERIN, J. L., HIRATZKA, L. F., JACOBS, A. K., NISHIMURA, R., ORNATO, J. P., PAGE, R. L. & RIEGEL, B. (2005) ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation 20, 112, e154-e235 JAPP, A. G. & NEWBY, D. E. (2008) The apelin-APJ system in heart failure: pathophysiologic relevance and therapeutic potential. Biochemical Pharmacology 75, 1882-1892 JOUGASAKI, M., GRANTHAM, J. A., REDFIELD, M. M. & BURNETT JR., J. C. (2001) Regulation of cardiac adrenomedullin in heart failure. Peptides 22, 1841-1850 JOUGASAKI, M., LESKINEN, H., LARSEN, A. M., LUCHNER, A., CATALIOTTI, A., TACHIBANA, I. & BURNETT JR., J. C. (2003). Ventricular cardiotrophin-1 activation precedes BNP in experimental heart failure. Peptides 24, 889-892 JOURDAIN, P., JONDEAU, G., FUNCK, F., GUEFFET, P., LE HELLOCO, A., DONAL, E., AUPETIT, J. F., AUMONT, M. C., GALINIER, M., EICHER, J. C., COHEN-SOLAL, A. & JUILLIERE, Y. (2007) Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure: the STARS-BNP Multicenter Study. Journal of the American College of Cardiology 49, 1733-1739 KANNO, N., KUSE, H., KAWASAKI, M., HARA, A., KANO, R. & SASAKI, Y. (2007) Effects of pimobendan for mitral valve regurgitation in dogs. The Journal of Veterinary Medical Science 69, 373-377 KAYE, D. M., LEFKOVITS, J., JENNINGS, G. L., BERGIN, P., BROUGHTON, A. & ESLER, M. D. (1995) Adverse consequences of high sympathetic nervous activity in the failing human heart. Journal of the American College of Cardiology 26, 1257-1263 KEATING, G. M. & GOA, K. L. (2003) Nesiritide: a review of its use in acute decompensated heart failure. Drugs 63, 47-70 KNOWLEN, G. G., KITTLESON, M. D., NACHREINER, R. F. & EYSTER, G. E. (1983) Comparison of plasma aldosterone concentration among clinical status groups of dogs with chronic heart failure. Journal of the American Veterinary Medical Association 183, 991-996 KVART, C., HÄGGSTRÖM, J., PEDERSEN, H. D., HANSSON, K., ERIKSSON, A., JARVINEN, A. K., TIDHOLM, A., BSENKO, K., AHLGREN, E., ILVES, M., ABLAD, B., FALK, T., BJERKFAS, E., GUNDLER, S., LORD, P., WEGELAND, G., ADOLFSSON, E. & CORFITZEN, J. (2002) Efficacy of enalapril for prevention of congestive heart failure in dogs with myxomatous valve disease and asymptomatic mitral regurgitation. Journal of Veterinary Internal Medicine 16, 80-88 LAINCHBURY, J. G., BURNETT JR., J. C. , MEYER, D. & REDFIELD, M. M. (2000) Effects of natriuretic peptides on load and myocardial function in normal and heart failure dogs. American Journal of Physiology. Heart and Circulatory Physiology 278, H33-H40 MACDONALD, K. A., KITTLESON, M. D., MUNRO, C. & KASS, P. (2003) Brain natriuretic peptide concentration in dogs with heart disease and congestive heart failure. Journal of Veterinary Internal Medicine 17, 172-177

10

JSAP801.indd 10

MAGGA, J., VUOLTEENAHO, O., TOKOLA, H., MARTTILA, M. & RUSKOAHO, H. (1998) B-type natriuretic peptide: a myocyte-specific marker for characterizing load-induced alterations in cardiac gene expression. Annals of Medicine 30 (Suppl. 1), 39-45, 39-45 MAISEL, A., MUELLER, C., ADAMS JR., K. , ANKER, S. D., ASPROMONTE, N., CLELAND, J. G., COHEN-SOLAL, A., DAHLSTROM, U., DEMARIA, A., DI SOMMA, S., FILIPPATOS, G. S., FONAROW, G. C., JOURDAIN, P., KOMAJDA, M., LIU, P. P., MCDONAGH, T., MCDONALD, K., MEBAZAA, A., NIEMINEN, M. S., PEACOCK, W. F., TUBARO, M., VALLE, R., VANDERHYDEN, M., YANCY, C. W., ZANNAD, F. & BRAUNWALD, E. (2008) State of the art: using natriuretic peptide levels in clinical practice. European Journal of Heart Failure 10, 824-839 MARCONDES-SANTOS, M., STRUNZ, C. M. & LARSSON, M. H. (2006) Correlation between activation of the sympathetic nervous system estimated by plasma concentrations of norepinephrine and Doppler echocardiographic variables in dogs with acquired heart disease. American Journal of Veterinary Research 67, 1163-1168 MAYER, S. A., DE LEMOS, J. A., MURPHY, S. A., BROOKS, S., ROBERTS, B. J. & GRAYBURN, P. A. (2004) Comparison of B-type natriuretic peptide levels in patients with heart failure with versus without mitral regurgitation. The American Journal of Cardiology 93, 1002-1006 MCGINLEY, J. C., BERRETTA, R. M. & CHADUHARY, K. B. (2007) Impaired contractile reserve in severe mitral valve regurgitation with a preserved ejection fraction. European Journal of Heart Failure 9, 857-864 MILLER, A. H., NAZEER, S., PEPE, P., ESTES, B., GORMAN, A. & YANCY, C. W. (2008) Acutely decompensated heart failure in a county emergency department: a double-blind randomized controlled comparison of nesiritide versus placebo treatment. Annals of Emergency Medicine 51, 571-578 NISHIDA, H., HORIO, T., SUZUKI, Y., IWASHIMA, Y., KAMIDE, K., KANGAWA, K. & KAWANO, Y. (2008) Plasma adrenomedullin as an independent predictor of future cardiovascular events in high-risk patients: comparison with C-reactive protein and adiponectin. Peptides 29, 599-605 OPIE, L. H. (2002) The neuroendocrinology of congestive heart failure. Cardiovascular Journal of South Africa 13, 171-178 OYAMA, M. A., FOX, P. R., RUSH, J. E., ROZANSKI, E. A. & LESSER, M. (2008) Clinical utility of serum Nterminal pro-B-type natriuretic peptide concentration for identifying cardiac disease in dogs and assessing disease severity. Journal of the American Veterinary Medical Association 232, 1496-1503 PEACOCK, W. F., HOLLAND, R., GYARMATHY, R., DUNBAR, L., KLAPHOLZ, M., HORTON, D. P., DE LISSOVOY, G. & EMERMAN, C. L. (2005) Observation unit treatment of heart failure with nesiritide: results from the proaction trial. The Journal of Emergency Medicine 29, 243-252 PEDERSEN, H. D. (1996) Effects of mild mitral valve insufficiency, sodium intake, and place of blood sampling on the renin-angiotensin system in dogs. Acta Veterinaria Scandinavica 37, 109-118 PEDERSEN, H. D., KOCH, J., POULSEN, K., JENSEN, A. L. & FLAGSTAD, A. (1995) Activation of the renin-angiotensin system in dogs with asymptomatic and mildly symptomatic mitral valvular insufficiency. Journal of Veterinary Internal Medicine 9, 328331 PEDERSEN, H. D., OLSEN, L. H., MOW, T. & CHRISTENSEN, N. J. (1999) Neuroendocrine changes in Dachshunds with mitral valve prolapse examined under different study conditions. Research in Veterinary Science 66, 11-17 PFISTERER, M., BUSER, P., RICKLI, H., GUTMANN, M., ERNE, P., RICKENBACHER, P., VUILLOMENET, A., JEKER, U., DUBACH, P., BEER, H., YOON, S. I., SUTER, T., OSTERHUES, H. H., SCHIEBER, M. M., HILTI, P., SCHINDLER, R. & BRUNNER-LA ROCCA, H. P. (2009) BNP-guided vs symptom-guided heart failure therapy: the Trial of Intensified vs Standard Medical Therapy in Elderly Patients With

Journal of Small Animal Practice

•

Congestive Heart Failure (TIME-CHF) randomized trial. JAMA 301, 383-392 POUSSET, F., ISNARD, R., LECHAT, P., KALOTKA, H., CARAYON, A., MAISTRE, G., ESCOLANO, S., THOMAS, D. & KOMAJDA, M. (1997) Prognostic value of plasma endothelin-1 in patients with chronic heart failure. European Heart Journal 18, 254-258 PROSEK, R., SISSON, D. D., OYAMA, M. A., BIONDO, A. W. & SOLTER, P. F. (2004) Plasma endothelin-1 immunoreactivity in normal dogs and dogs with acquired heart disease. Journal of Veterinary Internal Medicine 18, 840-844 PUBLICATION COMMITTEE FOR THE VMAC INVESTIGATORS (Vasodilatation in the Management of Acute CHF) (2002) Intravenous nesiritide vs nitroglycerin for treatment of decompensated congestive heart failure: a randomized controlled trial. JAMA 287, 1531-1540 RADEMAKER, M. T., CHARLES, C. J., ESPINER, E. A., FRAMPTON, C. M., NICHOLLS, M. G. & RICHARDS, A. M. (2004) Combined inhibition of angiotensin II and endothelin suppresses the brain natriuretic peptide response to developing heart failure. Clinical science (London, England) 106, 569-576 RAY, L., MATHIEU, M., JESPERS, P., HADAD, I., MAHMOUDABADY, M., PENSIS, A., MOTTE, S., PETERS, I. R., NAEIJE, R. & MCENTEE, K. (2008) Early increase in pulmonary vascular reactivity with overexpression of endothelin-1 and vascular endothelial growth factor in canine experimental heart failure. Experimental Physiology 93, 434-442 RAY, S. G. (2006) Natriuretic peptides in heart valve disease. Heart 92, 1194-1197 RICHARDS, A. M., NICHOLLS, M. G., LAINCHBURY, J. G., FISHER, S. & YANDLE, T. G. (2002) Plasma urotensin II in heart failure. Lancet 360, 545-546 ROIG, E., PEREZ-VILLA, F., MORALES, M., JIMENEZ, W., ORUS, J., HERAS, M. & SANZ, G. (2000) Clinical implications of increased plasma angiotensin II despite ACE inhibitor therapy in patients with congestive heart failure. European Heart Journal 21, 53-57 RUSH, J. E., FREEMAN, L. M., BROWN, D. J., BREWER, B. P., ROSS JR, J. N. & MARKWELL, P. J. (2000) Clinical, echocardiographic, and neurohormonal effects of a sodium-restricted diet in dogs with heart failure. Journal of Veterinary Internal Medicine 14, 513-520 RUSSELL, F. D. (2008) Urotensin II in cardiovascular regulation. Vascular Health and Risk Management 4, 775-785 SAKATA, K., IIDA, K., MOCHIDUKI, N. & NAKAYA, Y. (2009) Brain natriuretic peptide (BNP) level is closely related to the extent of left ventricular sympathetic overactivity in chronic ischemic heart failure. Internal Medicine (Tokyo, Japan) 48, 393-400 SAKR, A., HAHN, P., DONOHUE, T. & GHANTOUS, A. (2008) Nesiritide in the initial management of acute decompensated congestive heart failure. Connecticut Medicine 72, 517-523 SANTOS, M. M., STRUNZ, C. M. & LARSSON, M. H. (2006) Correlation between activation of the sympathetic nervous system estimated by plasma concentrations of norepinephrine and Doppler echocardiographic variables in dogs with acquired heart disease. American Journal of Veterinary Research 67, 1163-1168 SASAGURI, M., NODA, K., TSUJI, E., KOGA, M., KINOSHITA, A., IDEISHI, M., OGATA, S. & ARAKAWA, K. (1999) Structure of a kallikrein-like enzyme and its tissue localization in the dog. Immunopharmacology 44, 15-19 SCHWEIGER, T. A. & ZDANOWICZ, M. M. (2008) Vasopressin-receptor antagonists in heart failure. American Journal of Health-System Pharmacy 65, 807-817 SILVER, M. A., MAISEL, A., YANCY, C. W., MCCULLOUGH, P. A., BURNETT JR., J. C., , FRANCIS, G. S., MEHRA, M. R., PEACOCK, W. F., FONAROW, G., GIBLER, W. B., MORROW, D. A. & HOLLANDER, J. (2004) BNP Consensus Panel 2004: a clinical approach for the diagnostic, prognostic, screening, treatment monitoring, and therapeutic roles of natriuretic peptides in

Vol 50 (Suppl. 1) • September 2009

•

© 2009 British Small Animal Veterinary Association

14/8/09 8:54:44 AM

Neurohormonal activation in DMVD

cardiovascular diseases. Congestive Heart Failure (Greenwich, Conn.) 10, 1-30 SISSON, D. D. (2004) Neuroendocrine evaluation of cardiac disease. The Veterinary Clinics of North America. Small Animal Practice 34, 1105-1126 STEWART, R. A., RAFFEL, O. C., KERR, A. J., GABRIEL, R., ZENG, I., YOUNG, A. A. & COWAN, B. R. (2008) Pilot study to assess the influence of beta-blockade on mitral regurgitant volume and left ventricular work in degenerative mitral valve disease. Circulation 118, 1041-1046 SUTTON, T. M., STEWART, R. A., GERBER, I. L., WEST, T. M., RICHARDS, A. M., YANDLE, T. G. & KERR, A. J. (2003) Plasma natriuretic peptide levels increase with symptoms and severity of mitral regurgitation. Journal of the American College of Cardiology 41, 2280-2287 SWEDBERG, K., CLELAND, J., DARGIE, H., DREXLER, H., FOLLATH, F., KOMAJDA, M., TAVAZZI, L., SMISETH, O. A., GAVAZZI, A., HAVERICH, A., HOES, A., JAARSMA, T., KOREWICKI, J., LEVY, S., LINDE, C., LOPEZ-SENDON, J. L., NIEMINEN, M. S., PIERARD, L. & REMME, W. J. (2005) Guidelines for the diagnosis and treatment of chronic heart failure: executive summary (update 2005): The Task Force for the Diagnosis and Treatment of Chronic Heart Failure of the European Society of Cardiology. European Heart Journal 26, 1115-1140 TANG, W. H. & FRANCIS, G. S. (2005) Neurohormonal upregulation in heart failure. Heart Failure Clinic 1, 1-9

Journal of Small Animal Practice

JSAP801.indd 11

•

TANG, W. H., VAGELOS, R. H., YEE, Y. G., BENEDICT, C. R., WILLSON, K., LISS, C. L. & FOWLER, M. B. (2002) Neurohormonal and clinical responses to high- versus low-dose enalapril therapy in chronic heart failure. Journal of the American College of Cardiology 39, 70-78 TARNOW, I., OLSEN, L. H., KVART, C., HOGLUND, K., MOESGAARD, S. G., KAMSTRUP, T. S., PEDERSEN, H. D. & HÄGGSTRÖM, J. (2009) Predictive value of natriuretic peptides in dogs with mitral valve disease. Veterinary Journal 180, 195-201. TESSIER-VETZEL, D., TISSIER, R., CHETBOUL, V., CARLOS, C., NICOLLE, A., BENBARON, D., DANDRIEUX, J., THOULON, F., CARAYON, A. & POUCHELON, J. L. (2006) Diagnostic and prognostic value of endothelin-1 plasma concentrations in dogs with heart and respiratory disorders. Veterinary Medical Review 158, 783-788 TROUGHTON, R. W., FRAMPTON, C. M., YANDLE, T. G., ESPINER, E. A., NICHOLLS, M. G. & RICHARDS, A. M. (2000) Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet 355, 1126-1130 UECHI, M., SHIMIZU, A. & MIZUNO, M. (2002) Heart rate modulation by sympathetic nerves in dogs with heart failure. The Journal of Veterinary Medical Science 64, 1023-1029 VAN BENEDEN, R., GURNE, O., SELVAIS, P. L., AHN, S. A., ROBERT, A. R., KETELSLEGERS, J. M., POULEUR, H. G. & ROUSSEAU, M. F. (2004) Superiority of big endothelin-1

Vol 50 (Suppl. 1) • September 2009

•

and endothelin-1 over natriuretic peptides in predicting survival in severe congestive heart failure: a 7-year follow-up study. Journal of Cardiac Failure 10, 490-495 VARADARAJAN, P., JOSHI, N., APPEL, D., DUVVURI, L. & PAI, R. G. (2008) Effect of beta-blocker therapy on survival in patients with severe mitral regurgitation and normal left ventricular ejection fraction. The American Journal of Cardiology 102, 611-615 VILA, G., RESL, M., STELZENEDER, D., STRUCK, J., MAIER, C., RIEDL, M., HULSMANN, M., PACHER, R., LUGER, A. & CLODI, M. (2008) Plasma NT-proBNP increases in response to LPS administration in healthy men. Journal of Applied Physiology 105, 1741-1745 WARE, W. A., LUND, D. D., SUBIETA, A. R. & SCHMID, P. G. (1990) Sympathetic activation in dogs with congestive heart failure caused by chronic mitral valve disease and dilated cardiomyopathy. Journal of the American Veterinary Medical Association 197, 1475-1481 WIESE, S., BREYER, T., DRAGU, A., WAKILI, R., BURKARD, T., SCHMIDT-SCHWEDA, S., FUCHTBAUER, E. M., DOHRMANN, U., BEYERSDORF, F., RADICKE, D. & HOLUBARSCH, C. J. (2000) Gene expression of brain natriuretic peptide in isolated atrial and ventricular human myocardium: influence of angiotensin II and diastolic fiber length. Circulation 102, 3074-3079 YANAGAWA, B. & NAGAYA, N. (2007) Adrenomedullin: molecular mechanisms and its role in cardiac disease. Amino Acids 32, 157-164

© 2009 British Small Animal Veterinary Association

11

14/8/09 8:54:46 AM