clinical aspects of sympathetic activation and ... · 72a iacc vol. 22. no. 4 (supplement a) tkt6k:...

72A IACC Vol. 22. No. 4 (Supplement A) tkt6k: !993:72A-84A

Clinical Aspects of Sympathetic Activation and Withdrawal in Heart Failure

JOHN S. FLORAS, MD, DPHIL, FRCPC, FACC

Toronto, Ontario, Canada

M* nwbhus for generalized nsurohumoral acti- vatiaa lo hsart Mars lnclude dscreassd input fhtm Wbitory bvoneeptor afkent ves&s and increased iDput from excitatory afkrent vessels ari&g from arterM chemoreceptors, skeletal muscle nM&receptors or the hmgs. Nat all subjects with left ventriadar dysfktion have ~KIVMHJ sympathetic nerve activity, but the magnkde of sympatho~~l activation appsars to inde= pendently predh4 survival. This association suggssts both a caus= ative msdmnhm linking sympathetic activation with adverse outcome and a therapeutic 0pporMiQ to hnprove the progno& of such patients by inbiwting central sympathetk outflow. . m sympathetic activation is not unique to heart faihue, and its fim&mal co- appsartobebothorgan- and anulitionqscitic. Sympathetic activation is present in othsr dkrderssuchasmiM~,cirrhosisandagingthatdo MltsbalEthedhIlpNJglW&dMllge!khemdMhWe.The adverse ekts ofadrenergic activation on the dii myocar- di~maybeafunctionofthemagnitudeandthnecourseof

Congestive heart failure has been described as a condition of generalized neurohumoral excitation, characterized by activation of the sympathetic nervous and renin-angiotensin systems, increases in plasma vasopressin concentration, and parasympathetic withdrawal (l-3). Because the magnitude of sympathoneural activation in congestive heart failure appears to predict survival (the annual mortality rate of patients with venous plasma norepinephrine concentrations 900 pg/ml may exceed 70%) (3-J), the role of the sympathetic nervous system in its pathophysiology has received particular attention (1-3.6-8). Despite this attention, two critical questions remain unresolved: 1) Does the inverse

From the Division of Cardiology, Toronto Hospital and the Centre for Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada. This study was supported by OperaGw Grants from the Heart and Stmke Foundationuf Ontario, Toronto and the Medical Research Council ofCanada. Ottawa, Ontario. Dr. Floras is the recipient of a Career Scientist Award fk the Ministry of Health of the Rovhwe of Onlario, Toronto. The opinions expressed in this review are those of the author and not of the Ministry.

Manuscript received September 13, 1992; revised manuscript received February 26,19!& accepted March 3,1993.

Address Dr. John S. Fkss, Division of Cardiology, I2 EN-234, Toronto General Hospital, 200 Elizabeth Street, Toronto, On- tario. Canada. IW 2C4.

01993 by the American Collqte of Cardiology

Parasympathetic

hmeases in cardiac sympathetic nerve activity, the mechanical and ektrophysiologic consequences of nonuniform abnormalities of sympathetic hmervathm in the Ming heart and the absence! of spscitlc c0untervailing mecbisms present in other conditions also &rack&d by hased sympathe& trak. The hypothe. ses that activation of adrenergic drive to the dkased myocardim is the causative mechanism linking sympathosxdtation to adverse outcome and that h~terventions that inbiiit sympathetic outtlow to the heart will hnprove the prognosis of patients witb congestive hsart Mbwe have not beg specitkally tested. Greater under- standh~ of the mechanisms responsiile for the heterogeneity of sympathetic activation in response to ventricular dysfunction, for cardiac-specik and generakd activation of the sympathetic nsrvous system and for the sthuulation or suppression of counter- vailing mechanisms capable of resisting its adverse ekts is fundamental to the development of better therapies for congestive heart tMhu-e.

(J Am CoU Cm&o1 19313;22[Supplement A]:72A-84A)

relation between plasma norepinephrine concentrations and prognosis indicate a causal relation between sympathetic activation and mortality ?, and 2) will interventions that inhibit sympathetic activity improve outcome?

In this review I propose 1) to examine briefly manifesta- tions of sympathetic activation and parasympathetic withdrawal in humans with left ventricular dysfunction, mechanisms that may be responsible for these abnormalities, and for the potential adverse effects of adrenergic activation on the diseased myocardium and peripheral circulation in congestive heart failure, and 2) :o develop the following con- cepts: a) not all subjects with left ventricular dysfunction have increased sympathetic nerve activity; b) sympathetic activation is not unique to heart failure; and c) many of the mechanisms contributing to sympathetic activation in heart failure are functionally rather than structurally impaired and are potentially amenable to modulation. I will conclude with the proposal that activation of adrenergic drive to the diiased myocardium may be the causative mechanism linking sympathoexcitation and this adverse outcome. If so, future therapeutic interventions should specifically address the hypothesis that inhibiting sympathetic drive to the heart will improve the prognosis of patients with congestive heart failure.

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Pigure 1. Assessment of sympathetic and parasympathetic function in humans. Sympa- thetic function: arterial (A) or venous (V) plasma norepinephtine (PNE) and epinephrine (PE) concentrations (opper left); sympathetic nerve traific to muscle (MSNA) or skin (lower left); total body norepinephrine ([3H]NE) spillover or regional norepinephrine spillover across the heart (A = aorta or arterial; CS = coronary sinus) (upper right!, kidney (lower right) or leg (lower left); spectral analysis of heart rate variability (SA-HRV) (upper right). Parasympathetic function (upper tight): bradycardic response to phe- cylephrine (baroreflex sensitivity; BRS); spectral analysis of heart rate variability (SA- HRV).

Sympathetic and Parasympathetic Nervous Systems in Heart Failure

Sympathetic Nervous System

Assessment of sympathetic function in humans. Efferent postgaqglionic sympathetic nerve traflic may be assessed directly in humans by inserting microelectrodes into superficial nerves innervating muscle or skin (9) or indirectly by recording potential effector responses to the neurally released norepinephrine, such as heart rate j blood pressure or regionai blood flow and vascular resistance, or by quantitating venous or arterial catecholamine concentrations (10,l I), norepinephrine spillover into plasma (12) or heart rate variability (13-15) (Fig. 1).

Each of these methods assesses different aspects of sympathetic function and has its advantages and limitations. The latter should be considered carefully when interpreting information acquired with these techniques. Any potential link between sympathetic activity and hemodynamics wii1 be particularly tenuous in heart failure as a result of altered receptor responsiveness, cardiac and vascular structural alterations and concurrent activation of other vasoactive systems.

Norepinephrine concentrations can be determined simply and relatively inexpensively, but the values obtained have several shortcomings that limit their lusefulness as measures of sympathetic nerve traf8c in humans (10,ll). Only a small fraction of neurally released norepinephrine appears in plasma, and that which is measured does not reflect neurotransmitter release, but rather the balance between norepinephrine spillover into plasma and its clearance (12,16). Values are weighted toward regional (for exaaple, forearm) neurotransmitter spillover upstream from the sampling location (Fii. 1) (10,12). Because the sympathetic nervous system is capable of differential outflow, it should not be assumed that plasma norepinephrine concentrations measured from the antecubital vein provide an accurate estimate of sympathetic t&Tic to other hemodynamically important vascular beds (10-12). The issue of c!eaace is perhaps

most important in the context of heart failure. Becmse norepinephrine clearance is a function of regional blood flow

and inversely related to cardiac output (12), the interpreta- tion of any increase in plasma norepinephrine concentrations in heart failure will be ambiguous. Does it represent increased norepinephrine release or markedly impaired clearance in patients with poor left ventricular function?

To address this question, Esler et al. (12) developed a radiotracer method of assessing total body norepinephrine spillover as an indirect but close approximation of neural norepinephrine release in conscious humans. By adapting this technique to estimate regional (that is, organ-specific) norepinephrine spillover, these investigators (12,17) were also able to determine whether sympathetic activation in heart failure is generalized or directed specifically toward the heart, kidney or other vascular beds.

The major strength of the microneurographic technique is that it permits direct quantitation of sympathetic nerve tiring and its reflex control (9.18). Recordings are limited to superficial nerves, innervating muscular or cutaneous vascular beds. Because these nerves have diierent firing char- acteristics under basal conditions and in response to different stimuli, muscle sympathetic nerve burst frequency (influenced primarily by changes in baroreceptor afferent discharge) need not represent thing rates in other sympathetic nerves (9,lO). It is therefore worth noting that Wallin et al. (19) recently obtained evidence in normal subjects at rest that interindividual diierences in muscle sympathetic nerve discharge and cardiac norepinephrine spillover are proportional to each other. Their findings are consistent with the concept that a common mechanism influences the strength of sympathetic discharge to the heart and skeletal muscle.

The possibility that spectral analysis of heart rate vati- ability might provide a noninvasive estimate of sympathetic drive to the heart has stimulated considerable interest (Big. 1). However, there is as yet no clear consensus as to the optimal repr= _ ,sea&n of c&iac symphetic nerve t.diC

74A FLORAS SYMPATHETIC ACTIVATION IN HEART FAILURE

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by this method (14,15,20-22). Current analytic algorithms are limited by the need for heart rate variation for their application; such variation is lost in severe decompensated heart failure where sympathetic drive is highest, yet heart rate is fixed.

Evidence for gemahed qmpahmural acthtiOn in

heart hike. Plasma norepinephrine concentrations sam- pled during supine rest are elevated in patients with asymptomatic left ventricular dysfunction and increase further with the progression to overt congestive heart failure (1,3,23). At this later stage, total body norepinephrine spillover is on average double that of control subjects and norepinephrine clearance reduced by about a third (Fig. 2) (17).

Are these changes due to generalized increases in central sympathetic outflow or selective activation of sympathetic discharge to specific vascular beds? Certainly, the presenta- tion of the patient in severe decompensated congestive heart failure suggests generalized sympathetic activation: tachy- cardia, tachypnea, diaphoresis, pallor, agitation and renal sodium retention. Biochemical and microneurographic evidence of increased sympathetic outllow to the kidneys, heart, skeletal muscle and adrenal glands confirms this clinical impression.

In normal subjects, approximately 25% of total body norepinephrine spillover arises from the kidney and about 2% from the heart (12). These two organs contribute approximately 60% of the increase in the total body rate of appearance of norepinephrine in plasma in congestive heart failure: renal norepinephrine spillover increases 2- to 3-fold and cardiac norepinephrme spillover >lO-fold (Fii. 2) (12,17). Norepineptine spillover into the leg circulation also doubles (24). Because the radiotracer kinetic technique quantitates the rate at which neuronally released norepinephrine appears in plasma rather than sympathetic nerve tralRc or the rate of release of the neurotransmitter from sympathetic nerve endings, some of the increased spillover could be attributed to enhanced prejunctional modulation of neurotransmitter release by epinephrine (25) or augiotensin (261 or by decreased norepinephrine extraction within the neurovascular junction (12,27). This ambiguity was resolved by investigators (28,29) who obtained direct microneurographic evidence that efferent muscle sympathetic burst frequency is increased in cowestive heart failure @ii. 3) and

Figure 2. Total body, cardiac and renal norepinephrine spillover and norepinephrzne clearance from plasma in patients with congestive heart failure (CHF) and control subjects (CL +p < 0.02; **p c 0.002. 1 = liters. Adapted, with permission of the Au&can Heart Association, from Hasking et al. WI.

correlates positively with plasma norepinephrine concentrations.

Epinephrine concentrations are increased in severe heart failure, denoting heightened adrenal sympathetic nerve activity and medullary catecholamine release (3). Increased plasma concentrations provide the substrate for its neuronal uptake and incorporation into sympathetic vesicles along with norepinephrine (30). Esler et al. (30) have documented cardiac epinephrine spillover, averaging 2 ng/min or 2% of the corresponding norepinephrine spillover, in untreated congestive heart failure (but not in healthy volunteers at rest) and hiiher levels of neuronal epinephrine release from their gut, liver, lungs and kidneys. Approximately 25% of their total plasma epinephrine appearance rate was due to regional overflows from these organs. This observation demonstrates that epinephrine can assume a neurotransmitter role in heart failure, in addition to its traditional action as a circulating hormone (31). This transformation may have important functional consequences in this condition: as a humoral agent, the predominant effect of epinephrine is postjunction- ally mediated vasodilation, whereas as a wtransmitter, its predominant effect appears to be vasownstriction mediated by stimulation of prejunctional beb-adrenergic receptors that act to facilitate norepinephrine release (25).

Parasympathetic Nervous System The parasympathetic control of heart rate may be as-

sessed by quantitating the reflex bradycardic response to the pressor stimulus of phenylephrine (13) or by analysis of heart rate and its variability in the time (13) or frequency (14) domain (FE. 1). Each of these methods conilrms the initial demonstration by Eckberg et al. (32) of impaired parasympathetic control of heart rate in heart failure (20-22,33). Although low heart rate variability appears to be an inde pendent risk factor for mortality after myoca&al infarction (34), the prognostic importance of this abnormality in patients with heart failure has not been clearly established.

Similarly, the pathophysiologic implications of defective parasympathetic control of heart rate have not been fully investigated. It has been proposed that alterations in the parasympathetic component of heart rate variabiity spectra merely reflect greater sympathoexcitation in such patients

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Figure 3. Representative tracings of the electrocardiograms @per tradugs) and mean voltage neurograms of muscle sympathetic nerve activity (lower tracings) in three normal subjects (left) and three patients with heart failure (right). Adapted, with permission of the American Heart Associa- tion, from Leimbach et al. (2Q

4 01 oum1s=9 +&Age 27

(15). However, these are probably independent as well as interdependent alterations. They are independent in that impaired parasympathetic control of heart rate may precede sympathetic activation, as has been reported in subjects with idiopathic dilated cardiomyopathy (33). They are interdependent in that withdrawal of the restraining influence of acetylcholine on norepinephrine release (35) may explain why the relative increases in transcardiic norepinephrine spillover in heart failure are so much greater than those observed across other vascular beds, such as the kidney or the leg (17) (Fig. 3 and 4).

Mechanisms for Generalized Sympathetic Activation and Parasympathetic Withdrawal in Heart Failure

Generalized sympathetic activation and parasympathetic withdrawal in heart failure have been attributed to alterations in inhibitory and excitatory infhrences on brainstem vasomotor neurons. These mechanisms are illustrated in Figure 5. The contribution of impaired inhibitory barorecep tor reflex mechanisms to these abnormalities of autonomic reflex control has been reviewed in depth by Thames et al. (36). ABerent inputs from carotid sinus and aortic arch “arterial high pressure” and the cardiopulmonary “low pressure” mechanoreceptors are the principal inhibitory infhrences on sympathetic oudlow; discharge from arterial chemoreceptors and muscle “metaboreceptors” are the major excitatory inputs. The vagal limb of the baroreceptor heart rate reflex is also responsive to arterial baroreceptor

atferent input. The integrated response to these competing influences in normal subjects at rest may be characterized as a relatively low sympathetic discharge and relatively high heart rate variability. Compensatory vagal and sympatho-

Figure 4. I&al; + SE values for total body and regional norepinephrine spillover into plasma in 20 patients with congestive heart failure, 50 patients with essential hypertension and 35 patients with cirrhosis. Sign&ant increases from reference values ohtained from 28 healthy subjects (100%) are indicated by *p c 0.05 and **p < 0.01. Reproduced, with permission of the American Heart Associ- ation, from Esler et al. (12).

r- T CARDIAC FARWE

600 -

%A FLORAS SYMPATHETIC ACMVATION IN HEART FAILURE


Normai Afferenis

rlA m-7

CNS Efferents

_ .

Afl erents

Heart Failure CNS Efferents

t HearI

Figure 5. Mechanisms for generalized sympathetic activation and parasympathetic withdrawal in heart failure. Under normal conditions (top panel) inhibitory (-1 inputs from arterial and cardiopulmonary bamreceptor tierent nerves are the principal influence on sympathetic outflow. Parasympathetic control of heart rate is also under potent arterial baroreflex control. Efferent sympathetic trafiic and arterial catecholamines are low and heart rate variability high. As heart failure progresses (bottom panel) inhibitory input from arterial and cardiopulmonary receptors decreases and excitatory (+) input increases. The net response to this altered balance includes a generalized increase in sympathetic nerve trtic, blunted parasympathetic and sympathetic control of heart rate and impairment of the reflex sympathetic regulation of vascular resistance. Anterior wall ischemia has additional excitatory effects on efferent sympathetic nerve tralTtc. See text for details. Ach = acetylcholine; CNS = central nervous system; E = epinephrine; Nat = sodium; NE = norepinephrine.

neural responses to acute perturbations in blood pressure are appropriate and brisk (Fig. 5, top panel).

Asymptomatic left ventricular dysfunction and its progression to overt congestive heart failure disturb this balance (Fig. 5, bottom panel). As the principal stimuli to arterial baroreceptor tierent discharge (tbat is, systolic blood pressure, pulse pressure and the rate of rise of blood pressure) become blunted and as the sensitivity of arterial, atrial and ventricular mechanoreceptors to stretch diminishes, inhibitory input from arterial and cardiopulmonary receptors will decrease (2,37-39). In decompensated heart failure, excitatory input, ordiiy quiescent, may arise from arterial chemoreceptors, skeletal muscle metaboreceptors and the lungs (37). Central regulation of parasympathetic outflow is also attenuated (40). The net response to this shift in the balance between inhibitory and excitatory atferent input includes a generalized increase in basal sympathetic outflow,

parasympathetic withdrawal, blunted reflex parasympathetic and sympathetic control of heart rate and impairment of the reflex sympathetic reguhtion of vascular resistance (2,18,37).

Heterogeneity of Sympathetic Activation in Heart Failure

Nonetheless, many individuals with left ventricular dysfunction lack evidence for sympathetic activation (1,4,33, 41). Viquerat et al. (42) documented arterial norepinephrine concentrations within their normal range in about one-third of their subjects with heart failure. The initial Studies of Left Ventricular Dysfunction (SQLVD) report (23) on baseline neurohormonal data described venous plasma norepinephrine concentrations below the median value for control subjects in -25% of patients recruited to the asymptomatic arm and in about 15% of patients recruited to the treatment

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Table 1. Some Potential Explanations of Variations in Sympathetic Werve .4ctivity in Patients With Heart Failure

Patient age Stage of disease Severity of disease Therapeutic interventions

Sympathoexcitatory: sodium restriction, diuretic drugs, nonspecific vasodilators

Sympathoinhibitory: digitalis glycosides, beta-adrenergic antagonists, converting enzyme inhibition, physicai conditioning

Coexisting disurders Sympathoexcitatory: ischemic heart disease, sleep-related breathing

disorders Sympathoinhibitory: autonomic neuropathy

arm of this study. The majority of the young subjects with asymptomatic dilated cardiomyopathy that we have studied have muscle sympathetic nerve activity and plasma norepinephrine concentrations similar to those of age-matched normal volunteers (41).

Why is there such intersubject variation in sympathetic nerve activity in heart failure? Several factors could contribute to these variations in sympathetic traflic in patients with left ventricular dysfunction. Some of the more &ious examples appear in Table 1.

Stage and severity of disease. Abboud et al. (43) described three phases of autonomic disturbance in heart failure. In the early stage, decreased cardiac output activates the sym- pathoadrenal and renin-angiotensin systems reflexively. In the middle stage, compensatory hypervolemia and cardiac enlargement stimulate baroreceptor afferent vessels, causing reflex suppression or normalization of sympathetic nerve activity. In the final stage, the restraining influence of cardiac and arterial baroreceptor tierent vessels on the sympathetic nervous system and the renin-angiotensin systems is impaired, resulting in generalized neurohumoral activation (Fig. 5).

acutely or chronically through reflexive mechanisms, independent of any coexisting left ventricular dysfunction (39,44). Efferent sympathetic nerve activity could increase or decrease, &pending OG the nature and anatomic location of this insult. Prior myocardial infarction will interrupt the course of mechanoreceptor input to vagal tierents with inhibitory effects on sympathetic outfiow (44,45) (Fii. 5). Although not depicted in Figure 5, anterior wall &hernia elicits reflex sympathoexcitation by stimulating sympathetic aRerent nerves (39,46-49) and, if arterial blood pressure decreases during this intervention, by unloading sinoaortic baroreceptors (50), whereas ischemia involving-the infero- posterior wall of the left ventricle evokes a depressor reflex (39,47,48,51,52). Thus, it may not be appropriate to present data on ischemic and idiopathic dilated cardiomyopathy as if they arose from a common mechanism. Much of the evidence for increased sympathetic nerve t&c to muscle in congestive heart failure arises from studies of older patients with ischemic heart disease (28,29). Contrary evidence from young subjects with compensated idiopathic dilated cardiomyopathy (33,41) suggests that the cause of heart Wure may alsc influence the time course or magnitude of sympathetic activation in patients with lefi ventricular dysfimctioo and, possibly, its adverse effects on the failing heart. For example, Bristow et al. (53) have described important functional differences in components of the beta-adrenergic receptor-G protein-adenylate cyclase complex between ischemic and idiopathic dilated cardiomyopathy.

Ferguson et al. (29) have quantitated disease severity with the use of balloon-tipped thermotiution catheters in their study patients. They identified reduced cardiac performance and increased cardiac filling pressures as character- istics of patients with increased muscle sympathetic nerve activity. In contrast to Viquerat et al. (42), wh3 did not uncover any convincing relation between arterial norepinephrine concentrations and the hemodynamic status of their patients, sympathetic burst fi=equency in the study of Ferguson et al. (29) was inversely related to lefi ventricular stroke work index and stroke volume index and directly related to pulmonary artery mean and diastolic pressures. The latter observation is particularly intriguing because it raises the possibiity that mechanisms capable of sensing the severity of heart failure are preserved at this stage of the disorder @beit responding paradoxically) and are potentially amenable to modulation.

&&sting disorders: is&emie heart disease. Myocardial infarction or ischemia can influence sympathetic outffow

Coexisting disorders: obstructive sieep apnea. Sympa- thetic withdrawal during sleep typically results in a decrease in blood pressure of 20% to 25% from average waking levels (54-56). Heart failure is associated with briefer sleep duration, interrupted sleep and attenuation of the awake-asleep difference in blood pressure (57,58). Many patients with congestive heart failure also suffer from sleeprelated breathing disorders, includmg obstructive sleep apnea (57). Apnea, hypoxia and hypercapnia, which develop recmrently in obstructive sleep apnea, can cause profound increases in muscle sympathetic nerve activity (59-61). Such disturbances in breathing during sleep will adversely alter afterload in the failing heart by generating extreme negative swings in intrathoracic pressure (57) and by preventing the normal nocturnal reductions in sympathetic drive and blood pressure (56j. These noctlurnal abnormalities may stimulate the development of left ventricular hypertrophy (62). Obser- vations from our own (41) and other (63) laboratories raise the possibility that apneic episodes during steep t$W a sustained non-barorefiex-mediated increase in central sympathetic outiow that carries over into the daytime when subjects are awake and breathing spontaneously. unremit- ting exposure by day and at night to such sympathoexcitation could contribute synergistically to the dcve!opment or aggravation of congestive heart failure, but would not be responsive to conventional pharmacologic treatment.

%A FL0RA.s SYMPATHETIC ACTIVATION IN HEART FAILURE


Table 2. Potential Adverse Effects of Sympathetic Activation in Heart Riilure

cardiac Decreased betbndrenergic receptor responsiveness

Myowe hypertrophy Myocyte necrosis and fibrosis Nonuniform depletion of norepinephrine stores Nonuniform &struftiw of sympathetic innervation Arrhythnriap Imp&d diastolic function Impaired systolic function

Renal Increased tubular reabsorption of sodium Activation of &tkangiotensio system Increased renal vascular resistance Attenuated response to natriuretic factors

vasculiu Neurogenic vasoconstriction Vascular hypertrophy

Adverse l#ects of Adrenergic Activation on the Diseased Myocardium and Per&heral Circulation

AIIY supportive effect of this generalized increase in central sympathetic outflow on the heart and peripheral circulation in congestive failure is eventually superseded by a number of functional organ-specific consequences with potentially adverse implications (Table 2, Fig. 5). Myoerudium. Daly and Sole (7) reviewed the time course

of changes in myocardial sympathetic innervation and catecholamine content with the initiation and progression of experimental heart failure. In the hamster model of dilated cardiomyopathy, early increases in cardiac norepinephrine turnover, tyrosine hydroxylase and dopamine beta-hydroxylase activity and cardiic dopamine stores are followed by depletion of myocardial norepinephrine content and destruction of sympathetic nerve terminals. Other con- tributors to this symposium have discussed in detail the adverse effects of adrenergic drive on cardiac structure and function. These include downregulation of myocardial betar- adrenergic receptor number, decreased beta-adrenergic responsiveness to endogenous or exogenous agonists (64), trophic and toxic effects on cardiac myocytes (65), exacer- bation of arrhythmias predisposing to sudden death and impairment of ventricular diastolic and systolic function (Table 1). Daly and Sole (7) placed particular emphasis on the topography of altered myocardial norepinephrine content and sympathetic innervation in experimental heart failure; these investigators postulated that nonuniform distribution of these derangements would disturb the temporal coordination of mechanical contraction and relaxation, alter the dispersion of refractoriness and the duration and contig- uration of the cardiac action potential and consequently exacerbate any underlying mechanical or electrophysiologic dysfunction in such patients.

paipheral &culatlon. Excessive sympathetic drive to the periphery can exacerbate the hemodynamic derange

ments of heart failure by increasing both preload and afterload (Fig. 5). For example, elevated elferent renal sympathetic nerve activity will exacerbate congestion by activating the renin-angiotensin system, stimulating tubular reabsorption of sodium and water, decreasing renal blood Uow and glomerular f&ration rate and blunting the renal responsiveness to atrial natriuretic peptide (2,66,67). Augmented adrenergic drive to muscle will sustain afterload at inappropri- ately high levels, whereas secondary hypertrophy of smooth muscle in resistance vessels will ampliiy neurogenic vasoconstrictor responses to sympathetic input (7,68,69). Reduc- tions in muscle blood flow by these mechanisms below levels required to meet local metabolic demands may increase sympathetic outflow reflexively, particularly during exercise, by stimulating excitatory metaboreceptor afferents (Fig. 5) and possibly contribute to the impaired functional capacity of such patients (2,69).

In summary, there are many cardiac and peripheral mechanisms by which sympathetic activation could adversely inlluence prognosis in heart failure. However, any attempt to establish a causal relation between sympathetic activation and mortality on this basis must contend with the awkward observation that sympathetic activation is not unique to heart failure, but is present in other disorders that do not share its poor prognosis.

Other Conditions of Generalized Sympathetic Activation

Sympathetic excitation and parasympathetic withdrawal are not specific to heart failure: There is biochemical or microneurographic evidence, or both, of increased sympathetic outflow to the kidneys, heart, skeletal muscle and adrenal glands in young subjects with borderline and mild essential hypertension (12,70-73), in patients with cirrhosis and ascites (12,74), in subjects with obstructive sleep apnea even when studied while awake (63) and in healthy elderly persons (70,75) (Fig. 6). Hypertension and aging are also characterized by impaired parasympathetic control of heart rate (76). Cardiac and renal norepinephrine spillover are 1.5 to 3-fold higher in young subjects with hypertension than in age-matched normotensive control subjects (12) (Fig. 4). Renal norepinephrine spillover is increased threefold in patients with cirrhosis, whereas cardiac norepinephrine spillover is five to seven times higher than in control subjects (12) (Fii. 4). Indeed, subjects with cirrhosis and ascites display a profile of generalized neurohumoral activation not unlike that of the patient with heart failure (74,77): Atrial natrhrretic factor is increased (78), the heart rate is _ ?pid, and varies little, and increases in muscle sympathetic nerve activity correlate positively with elevated venous norepinephrine and epinephrine concentrations and with plasma renin activity (74).

The reflex and central mechanisms responsible for increased sympathetic outflow and parasympathetic with-

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Figure 6. increased muscle sympathetic nerve activity (MSNA) is not specific to heart failure. Reproduc- tions of 40-s segments on the electro- cardiogram (ECG) and mean voltage neurograms of muscle sympathetic nerve activity in four of our subjects with other conditions of sympathetic activation: a healthy elderly P70 years) subject (upper Mt) and three young (~40 years) subjects with, re- spectively, mild hypertension, sleep apnea @udied while awake) and cirrhosis with ascites.

MSNA

Sleep Apnea

MSNA

drawal differ in each of these conditions, yet the integrated neural output received by important target organs is quah- tatively similar (that is, there is no characteristic neural signature that is specific for each of these particular patho- geneses) (Fig. 6). This observation raises two interesting questions. First, if increased central sympathetic outflow is common to each of these conditions, why are its potential adverse effects in heart failure (Table 2) not shared by other conditions characterized by sympathetic activation? The pathologic consequences of this nonspecific neural stimulus appear to be condition- and organ-specific. Young subjects with hypertension, healthy elderly patients and patients with cirrhosis and ascites diBer greatly in their hemodynamic profiles and display a wide range of cardiac, renal and vascular responses to the burden of increased sympathetic outflow. For example, the early “hyperadrenergic” stage of essential hypertension in young subjects is characterized by increased cardiac output (79,80) and despite increases in their arteriolar waMumen ratio, which should enhance vascular responsiveness to norepinephrine and other vasocon- strictors @I), bmchiai artery blood ffow is increased through a be&-adrenergic mechanism (81). Patients with cirrhosis and ascites tend to have increased rather than decreased cardiac output, peripheral vasodilation rather than constric- tion and blunted vascuhrr responsiveness to norepinephrine (82-85). These hemodynamic patterns are quite different from those seen in patients with ventricular dysfunction. Second, if there is a causal relation between sympathetic activation and mortality, why is it not manifest in these other conditions? Increased plasma norepinephrine concentrations, for example, do not confer the same dim prognosis on the healthy elderly or persons with primary hypertension as they do in patients with heart failure.

Several factors could account for such diversity: The magnitude of sympathetic activation. organ-specific responses to increased adrenergic drive, and the presence or absence of amplifying or opposing forces, unique to each condition.

Mild Hypertensioa I

I J

Cirrhosis With Ascites

Ctrgau-specik respoums. Three important card&-specific factors are worth noting. First, and perhaps most fundamental, is that regardless of the etiology of ventricular dysfunction and in contrast to these other conditions, both the primary stimulus to and the target of increased cardiac sympathetic drive is a diseased myocardium. Second, the increase in cardiac norepinephrine spillover relative to that in other vascular beds appears to be greater in congestive failure than in cirrhosis or primary hypertension (12) (Fig. 4). Reasons for this observation have not been fully elucidated, but could include more intense neural drive to the heart, greater withdrawal of the inhibitory influence of a.cetylcho- line (35) and augmentation of the faciiitatory influence of epinephrine (3,30,3 I ,70) on cardiac norepinenhrine release and possibly (this issue remains controversial) decreased neuronal norepinephrine upiake (12,27,86&U). Third, the effects of prolonged intense adrenergic stimulation on myocardial norepinephrine stores and sympathetic nerve terminals are heterogeneous (7). The diseased heart, with its altered geometry and patchy distribution of fibrosis and necrosis, will be particulariy sensitive to any nonuniform destruction of sympathetic or parasympathetic innervation. Such pathologic inhomogeneity may have profound mechanical, electrophysiologic and prognostic implications for patients with heart failure (7).

The differing vascular responses to increased muscle sympathetic activity in congestive heart failure, mild hypertension and cirrhosis, described earlier, reinforce the concept that condition- or organ-specific factors may also am- plify or oppose neuroeffector transduction of this increased adrenergic drive. Neurogenic vasoconstriction Can be ampli- fied geometrically by structural changes in resistance vessels (68) and opposed by potent endothelially mediated vasodi- Iation (88). The latter mechanism is impaired in both byper- tension (89) and heart failure (90,91) and may be augmented in cirrhosis (92). On the basis of these observations, one could propose that interventions that improve endothehalIy mediated vas&on might benefit patients with congestive

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heart failure by countering the vasoconstrictor response to their increased sympathetic drive.

The response of the kidneys to increased renal sympathetic nerve activity (Fig. 5) appears to be more homoge- neous (66). We have documented an inverse relation between muscle sympathetic nerve activity and both the f?actional excretion of sodium (74) and the natrhuetic response to a 2-h infusion of atrial natrImtic peptide (67) in patients with cirrhosis and ascites. These derangements in renal function and responsiveness to atrial natrhuetic peptide appear common to both cirrhosis and congestive heart failure (67,93-95). However, increased renal sympathetic nerve activity alone cannot account for these changes; renal norepinephrine spillover is increased in young subjects with essential hypertension (12) (Fii. 4), but they do not sulfer from edema or ascites as a consequence.

In summary, neither the adverse effects detailed in Table 2 nor the poor prognosis of patients with heart failure can be attributed exclusively to increased central sympathetic outllow. The functional consequences of sympathetic activation appear to be condition- and organ-specific. Of these, the adverse effects of intense cardii sympathetic activation on a diseased myocardium may be most important, and interventions that preferentially attenuate adrenergic drive to the heart may be of particular benefit. Thus far, the hypothesis that inhibiting efferent sympathetic nerve activity will improve the prognosis of patients with congestive heart failure has not been tested directly.

Modulation of Sympathetic Activity in

Heart Failure

The only drugs shown to reduce the incidence of death in congestive heart faihue thus far are converting enzyme inhibitors and nonspecific vasodilators (96-99), but the mortality r3te irl treated patients remains disappointingly hii. In those with severe heart failure enrolled in the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) (97), the 6-month mortality rate was 48% in the placebo-treated group and 29% in the enal@-treated group (97). The impact of converting enzyme inhibition on survival of patients with less severe expression of their congestive heart failure has been modest: iu the SOLVD Treatment Study (9g), the mortality rate was 39.7% in the conventionally treated group and 35.2% in the enalapril- treated group (that is, mortality benefit was provided to only 4.51100 patients after 41 months of treatment, and in the SOLVD Prevention Trial (MO), converting enzyme inhibition attenuated the progression of asymptomatic left ventricular dysfunction to congestive heart failure but had no significant effect on mortality. .4lthough the positive effects of long-term converting enzyme inhibition on survival may be greatest in subjects with highest norepincphrine wncen- trations (3,5), the SOLVD neurohumoral substudy data presented by Benedict et al. (101) elsewhere in this sympo-

sium do not reveal any short-term or long-term effect of angiotensin-converting enzyme inhibition with enalapril on mean values for plasma norepinephrine concentrations. Thus, it is not clear whether sympathoinbibition is one of the mechanisms by which converting enzyme inhibition inter- rupts disease progression or improves the prognosis of asymptomatic or symptomatic patients.

The SOLVD, CONSENSUS and other recent trials have had a major positive impact on our understanding and management of congestive heart failure. These trials have also emphasized the need to develop additional interventions to improve the poor prognosis, even after treatment, of these patients. Packer (8) recently summarized the limitations of early attempts to antagonize the peripheral effects of neurally released norepinephrine. The alpha-l antagonist pra- zosin, for example, has no demonstrable effect on mortality (96) and, until recently clinicians have been reluctant to prescribe beta-adrenoceptor antagonists for such patients out of wncem that they will further impair contractile function. The principal drawback of this adrenoceptor antagonist approach is its limited objective, which is to shield the heart, kidney and peripheral vascadature from the potentially harmful eRects of neurally released norepinephrine rather than to attenuate sympathetic outllow to these organs. It is diicult to maintain a consistently effective shield with long-term treatment and, perhaps more important, the neuroeffector response to other neurotransmitters released by noradrenergic nerves innervating the heart will not be blocked by these antagonists. One such neurotransmitter is neuropeptide Y, a potent inhibitor of efierent vagal neurotransmission (102) and a wronary and peripheral vasoconstrictor with a more sustained duration of action than that of norepinephrine (103).

To attain additional benefit, it may be necessary to attenuate adrenergic drive directly by developing and apply- ing interventions that attenuate central sympathetic outllow or norepinephrine synthesis (104) or release. Neural norepinephrine release may be reduced by several distinct mechanisms: by augmention of inhibitory baroreceptor input, suppression of excitatory influences, inhibition of sympa- theric tral8c centrally and prejunctional inhibition of neurotransmitter release (Pi. 7).

Obviously, the lirst approach would not be feasible if reflex sympathetic activation due to baroreceptor dysfunction were an inevitable and irreversible consequence of heart failure. However, evidence from several sources indicates that the restraining influence of inhibitory arterial and cardiopulmonary mechanoreceptor tierents on sympathetic outllow is suppressed, rather than irreversibly damaged in congestive heart failure. For example, cardiac unloading with lower body negative pressure can evoke a reflex sympathoinhibitory response in some patients with congestive failure: this paradoxic observation has been attributed to a decrease in left ventricular end-diastolic volume and wall stress, a consequent increase in left ventricular fractional shortening and an inotropically mediated increase in ventric-


Figure 7. Attenuation of sympathetic outflow in heart failure. Potential mechanisms include: 1) augmenting inhibitory baroreceptor input by sensitization or stimulation of arterial and cardiopulmonary baroreceptor afferents; 2) decreasing excitatory afferent input from arterial chemoreceptors, skeletal muscle or lungs: 3) central inhibition of sympathetic outiow; 4) inhibition of ganglionic neurotransmission; and 5) prejunctional inhibition of norepinephrine or epinephrine release. In addition, the neuroegector response to increased adrenergic drive can be blocked by alpha- and beta-adrenoceptor antagonists. Ab- breviations as in Figure 5.

FLORAS SYMPATHETIC ACTIVATION IN HEART FAILURE

81A

Afferents CNS Eff eren!s

uiar mechanoreceptor discharge (43,105). The arterial baroreflex control of heart rate also appears to be functionally rather than structurally impaired because it can be restored by treatment of decompensated heart failure by bed rest, salt restriction, diuretic drugs and vasodilators (such treatment may also blunt excitatory influences on sympathetic outflow) (106), by reversal of canine heart failure (107) or by heart transplantation in humans (108). Nonpharmaco- logic approaches should also prove effective: the benefits of long-term exercise training of selected subjects with congestive heart failure include reduction of total body norepinephrine spi!lover and normalization of the parasympathetic and sympathetic control of heart rate variability (109). Atria1 natriuretic peptide, which inhibits sympathetic outflow in normal subjects through either a central or a ganglionic mechanism (1 lo), also has inhibitory effects on norepinephrine and epinephrine release that are not attenuated in experimental canine heart failure (111); its potential sympathoinhibitory actions in congestive heart failure in humans remain to be explored.

Digitalis glycosides, angiotensin-converting enzyme inhibitors and beta-adrenoceptor antagonists may exert part of their beneficial actions in congestive heart failure throu& similar mechanisms. Activation of Na+, K+-ATPase at the neuronal membrane can cause acute peripheral baroreceptor resetting (112). Di$alis is said to cause a reflex sympathoin- hibition that has been attributed to sensitization of cardiopulmonary mechanoreceptors (113) (this observation has been disputed [ 1141) and in some subjects with congestive heart failure, digitalis normalizes the reflex vasodilator response to cardiac unloading (105). In experimental heart failure, ouabain also appears to sensitize arterial baroreceptor nerve endings (38). The effects of long-term treatment with digitalis glycosides on sympathetic nerve traEc have not been reported.

Angiotensin-converting enzyme inhibitors (and angiotensin II antsqonisis) improve the parasympathetic control of

heart rate (115) and should antagonize the facilitative effects of angiotensin II on central sympathetic outilow and inhibit norepinephrine release at the neuroe&tor junction, where it is subject to modulation by prejunctional angiotensin II receptors (26). Despite these potential sympathoinhibitory mechanisms, it has been diicult to demonstrate any short- term or long-term effect of angiotensin-converting enzyme inhibition with enalapril on mean values for plasma norepinephrine conceWations (101) or any inhibitory eEect of acute administration of captopril or enalaprilat on total body norepinephrine spillover in subjects with congestive heart failure (116). Thus, the mechanism or mechanisms responsible for the beneficial effect of long-term converting enzyme inhibition on survival remain open to investigation.

The role of beta-adrenergic receptor antagonists in dilated cardiomyopathy is discussed elsewhere in this symposium (117). In addition to shielding the heart against the potentially toxic effect of increases in neurally released or circulating catecholamines (Table 2), this class of drugs may dampen central sympathetic outllow (118). An additional benefit of beta-blockade may be that proposed by Daly and Sole (7): Beta-adrenergic blockade should improve the temporal coordination of excitation and contraction between innervated and denervated segments by restoring the unifor- mity of neural stimulation of the heart.

conclusions *

The time course over which organ-spectic or generalized sympathetic activity begins to increase after the develop ment of left ventricular dysfunction has not been characterized. Because the primary derangement in subjects with such dysfunction is cardiac, sympathetic drive ta the heart may be increased early in the course of this disorder before there is any obvious increase in muscle sympathetic burst frequency, total body norepinephrine spillover or plasma norepinephrine concentration. Activation of adrenergic

82A FLORAS SYMPATiiEsTIC ACTIVATION IN HEART FAILURE

JACC Vol. 22, No. 4 (Supplement A) October 1993:72A- MA

drive to tin diseased myocardium may be the causative tnechr;lllsm li&ittg sympathetic activation to adverse OBt-

come, and interventions that selectively modulate sympathetic outtlow to the heart may exert the greatest benefit, particularly if administered early before the development of generalixed sympathetic activation. In this respect, the recent observation by Bristow et al. (119) that beta- adrenoceptor blockade with carvedilol selectively attenuates adrenergic drive to the failing heart is particularly interesting and could serve as the basis for future tests of this concept.

Activation of the sympathetic nervous system appears to independently predict adverse outcome in patients with left ventricular dysfunction, but increased central sympathetic outflow is not specific for this condition. It is present in other disorders that do not share the dim prognosis of patients with congestive heart failure. The adverse effects of adrenergic activation on the diseased myocardium may be a function of the magnitude and time course of the increase in cardiac sympathetic nerve activity, the mechanical and electrophysiologic consequences of nonuniform abnormalities of cat&c innervation in the failing heart and the absence of specific protective countervailii forces present in other conditions also characterized by adrenergic activation. Furthermore, not all patients with left ventricular dysfunction have increased sympathetic nerve activity. Greater understanding of the mechanisms responsible for the heterogeneity of sympathetic activation in response to ventricular dysknc- tion, for cardiac-specific and generalized activation of the sympathetic nervous system and for the stimulation or suppression of compensatory mechanisms capable of resisting its adverse effects is fundamental to the development of better therapies for congestive heart failure.

References 1. Francis GS, GoMsmhh SR, Olivmi MT, Levine TB. Cohn JN. The

neurohumoral axis in congestive heart failure. Ann Intern Med 19&101: 376-7.

2. Hii AT, Dzau VJ, Cmager MA. Baroreceptor function in congestive heart tbihue: elfect on oeurohumoral activation and regional vascular .slstance. Ciilatloa 19lQ7S(suppl IV):IV-36-48.

3. Swedberg K, Eneroth P, Kjeksnus J, Whhemwen L. Hormones reguhtt- htg cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Ciilation 199@;82:1739-6.

4. Cohn JN, Levine TB, Olivari MT, et al. Plasma not@nephrine as a @rtde to prognosis in patients with congestive heart failure. N Engl J Med lw311:819-23.

5. Cohn JN. Simon A, Johnson G for the V-HeFT Study Group. Rehuion- ship of plasma oompinephrine and plasma renio activity to mortality io heart faihuu (abstr). Circulation 199l;&l(suppl II):II-310.

6. Massie BM, Swedbug K, Cohn JN. Is neurohormonal activation dele- terious to the long-term outcome of patients with congestive heart falhue? J Am Cdl Cardlol1988,12:547-58.

7. Daly PA, Sole MJ. Myocardial catecholammes and the pathophysiology of heart failure. Ciiuh~tlon l99th;82(suppl I)$35-43.

8. Packer M. Role of the sympathetic nervous system in chronic heart failure: a historical and phihwophical perspective. Circulation 1990; 82(suppl I):~-1-6.

9. Wallln BG, Faghts J. Peripheral sympathetic neural activity in conscious hmnans. Ann Rev Physioll988;50:565-76.

19. Fdkow 9, DiBona GP, Hjemdahl P, Toren PH. Wallin BG. Measure-

ments of plasma norepinephrhte concentrations itt human primq by- pertension: a word of caution on their applicability for assessing neurogenic contnitioos. Iiypettensloo 1983;5:399-493.

11. Floras J, Jones JV, Hassan MO, Osikowska BA, Sever PS, Sleight P. Failure of plasma norephwphrine to consistently rellect sympathetic activity in man. Hypertension 1%8:641-9.

12. E&r M, Jennings G, Korner P, et al. Assessment of human sympathetic nervous system activity from measurements of noreplnepbrine turnover. Hypertension 198&l 1:3-u).

13. Floras JS, Hassan MO, Jones JV, Oslkowska BA. Sever PS, Sleight P. Factors influencing blood pressure and heart tate variabiiy in hypertensive man. Hypertensioo 1988;11:273-81.

14. Mallii A, Paganl M, Lombardi F, Cerutti S. Cardiovascular neural reBthuio0 explored in the frequency domain. Circulation 1991;84:482- 92.

15. Kienxle MG, Fergusou DW, Birkett CL, Myers GA, Berg WJ, Mariano DJ. Clinical, hemodynamic and sympathetic neural correlates of heart rate variability in congestive heart Milure. Am J Cardio11992$&761-7.

16. Goldstein DS, Zimllchman R, Stull R. Keiser HR, Kopln Ll. Estimation of inttnsynaptlc oompinephtine conceotrations in humans. Hypertension l!uJ6#471-5.

17. Haskhtg GJ, Esler MD, Jemdngs GL, Burton D, Johns JA, Komer PI. Norepinephtine spillover to plasma in patients witb congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Ciitdati~n 1986;73:615-2’1.

18. Ferguson DW, Berg WJ, Roach PJ, Oren RM, Mark AL. Effects of beart failure on baroretlex control of sympathetic neural activity. Am J Can%01 1991$9:523-31.

19. Wallin BG, E&r M, Donvard P, et al. Simultaneous measurements of cardiac noradrenalme spillover and sympathetic outliow to skeletal muscle in hmnans. J Phvsiol 1992~453~4~58.

26. Saul JP, Arai Y, Be&r RD. Lilly LS, Colucci WS, Cohen RJ. Assessment of autonomic reguhttioo in chronic congestive heart failure by heart rate spectral analysis. Am J Cardiol1988;61:1292-9.

21. Binkley PF. Nunziata E, Haas GJ, Nelson SD, Cody RJ. Parosympa- thetic withdrawal ls an intekval component of autonomic imbalance in congestive heart falhtre: demonstration in humans subjects and veritica- tion in a paced canine model of ventricular failure. J Am Co11 Cardiol 1991;18%4-72.

22. Hoogenhuyxe DV, Weiosteht N, Martin GJ, et al. Reproducibility and relation to mean heart rate of heart rzte variabiity in normal subjects and in patients witb CotuJestive heart tailure secoodary to coronary artery d&a-e. Am J Cardiol19.9!;6&1668-76.

23. Francis OS, Benedict C, Johnstons DE, et al. Comparison of oeumen- docrioe activation in patients with telt ventricular dysfunction with and without congestive heart failure: a substudy of the Studies of I_& Ventricular Dysfunction (SOLVD). Circulation 199&82:1724-9.

24. Sullivan MJ, Kuhn CM, Charles HC. Negro-Villar R, Kennedy JE, Cobb FR Skeletal muscle adrenerglc activation is increased at rest and during exercise in chmnic heatt failure (abstract). Circulation 1991;84(suppl H):H-74.

25. Floras JS, Ayiward PE, Victor RG, Mark AL, Abboud FM. Epinephrine facilitates neurogenic vasoconstrictioo in humans. J Clin Invest 1988$1: 1265-74.

26. Zimmerman BG. Actions of angioteosin on adrenetpic nerve endings. Fed Pmc 1978;37:199-262.

27. Pet& MC, Nayler WG. Uptake of catechohrmines by humao cardiac muscle in vitro. Br Heart J lm413336-9.

28. Lelmbach WN, Wallin BG, Victor RG, Aylward PE. Sundlof G, Mark AL. Direct evidence from intraneural recorvEht.gs for increased central sympathetic outllow in patients with hemt failure. Circuhttion lm.73: 913-g.

29. Ferguson DW, Berg WI, Sanders JS. Cliical and hemodynrmic correlates of sympathetic oerve activity in normal humans and patients with heart failure: evidence from diit mlcmneurographlc recordii. J Am Coil Cardioll999;36:1125-34.

30. Esler M, Eisenhofer G. Chin J, et al. Release of adrenaline from the human sympathetic nervous system. C.&I Autoo Re.s 1991;1:103-8.

31. Kassis E, Jacobsen TN, iNo~osen F, Amtorp 0. Sympathetic ret?ex control of skeletal muscle bii Row in patients with congestive heart failure: evidence for jHidreoergic circulatory control. Circulation 1986, 74529-38.

JACC Vol. 22. No. 4 (Supplement A) October 1993:72A-84A

32. Eckberg DL, Drabinsky M. Braunwald E. Defective cardiac parasym pathetic control in patients with heart disease. N Et~gl J Med 1971;285: 877-83.

33. Amorim DS, Datgie HJ. Heer K, et al. Is there autonomic impairment in congestive (dilated) cardiomyopathy? Lancet 1981;1:525-7.

34. Kleiger RE, Miller JP, Bigger JT, Moss AJ. for the Multicenter Postin- farction Research Group. Decreased hear! rate variability and its association with increased mortality after acute myocardial infarction. Am J Cardiol 1987;59:257-62.

35. Vanhoutte ?M. Levy MN. Prejunctional cholinergic modulation of adrenergic neurotransmission in the cardiovascular system. Am J Phys- iol 1%0;238:Ii2i5-81.

36. Thames MD, Kunigawa T. Smith ML, Dibner-Dunlap ME. Abnormali- ties of baroreflex cor!rol in heart failure. J Am Co11 Cardiol 1993; 22(suppl A):56A-Q

37. Ferguson DW. Barn...flex-mediated circulatory control in human heart failure. Heart Failure 1990k3-I I.

38. Wang W, Chen J-S, Zucker IH. Carotid sinus baroreceptor sensitivity in experimental heart failure. Circulation 1990,81:1959-66.

39. Halnsworth R. Reflexes from tlre heart. Physiol Rev 1991;71:617-58. 40. Porter TR. Eckberg DL. Fritsch JM. et al. Autonomic pathophysiology

in Seart fti!z patients: sympathetic-cholinergic interrelations. J Clin Invest 199085.1362 ?l.

41. Floras JS, kai K, Wigle ED, Daly P, Senn BLM. Sympathoneural prolile of patients with idiopathic dilated cardiomyopathy (IDCM) tab- stract). Can J Cardiol 1991;7: lO4A.

42. Viquerat CE, Daly PA, Swedberg K. et al. Zndogenotis catecholmine levels in chronic heart failure. Am J Med 1985;78:455-9.

43. Abboud FM, Thames MD. Mark AL. Role of cardiac tierent nerves in regulation of circulation during coronary occlusion and heart failure. In: Abboud FM, Fowrrd HA, Gilmore JP, Reis DJ. eds. Disturbances in Neurogenic Con:ml of the Circulation. Baltimore, Williams & Wilkins, 1981:65-86.

44. Zipes DP. Influence of myocardial ischemia and infarction on autonomic innervation of heart. Ciiulation 1890;82: 1095-105.

45. Minisi AJ, Thames MD. Effect of chronic myocaidial infarction on vagal cardiopulmonary baroreflex. Circ Res 1989;65:3%-405.

46. Brown AM, Malliani A. Spinal sympathetic reflexes initiated by corn nary receptors. J Physiol Lond l!Pl;212:685-705.

47. Webb SW, Adgey AA, Pantridge JF \utonomic disturbance at onset of acute myocardii infarction. Br Mc; J 1971;3:89-92.

48.

49.

50.

51.

52.

53.

54.

55.

56.

57.

Weaver-LC, Danos LM, Oehl RS. Meckler RL. Contrasting reflex inlluences of cardiac nerves during coronary occlusioll. Am J Physiol 1981;24O(Heart Circ Physiol9):H620-9. Lombardi F. &alone C. Della Bella PD. Malafatto G. Pagani M, Mallianl A. Global versus regional myocardial ischemia: diierences in cardiovascular and sympathetic responses in cats. Cardiovasc Res 1%18:14-23. Felder RB. Thames MD. Interaction between cardiac receptors and sinoaortic baroreceptors in the control of efferent cardiac sympathetic nerve activity during myocardial ischemia in dogs. Cii Res 1979;45: 128-36. Thames MD, 4bboud FM. R&x inhibition of renal sympathetic nerve activity during myocardial ischemia mediated by left ventricular recep tars with vagal alferents in dogs. J Clin Invest 1979;63:395-402. Wei N, Markis JE. Malagold M, Braunwald E. Cardiovascular reR:xes stimulated by perfusion of ischemic myocardium in acute myocardii infarction. Circulation 1%3;67:7%-801. Bristow MR, Anderson FL, Port JD. et al. Differences in padrenergic neuroeffector mechanisms in ischemic versus idiopathic dilated cardiomyopathy. Circulation 199I;84:1024-39. Floras IS, Sleight P. Ambulatory monitoring of blood pressure. In: Sleight P, Jones JV, eds. Scientific Foundations of CardiolT.gy. Londo.:: Heineman, 1983:155-64. Linsell CR, Lightman SL, Mullen PE. Brown MJ, Causon RC. Circadian rhythms of epinephrine and norepinephrine in man. J Ctin Endocrinol Metab 1985;60:1210-5. Somers VK, Dyken ME, Mark AL. Abboud FM. Sympathtic-nerve activity during sleep in normal subjects. N Engl J Med 19332gz303-7. Malone S, Liu PP. Holloway R, Rut&ford R, Kie A, Bradley TD.

58.

59.

60.

61.

62.

63.

64.

65.

66.

67.

68.

69.

FLORAS SYMPATHETIC ACTIVATION IN HEART FAILURE

B3A

Obstructive sleep apnoea in patients with dii cardiomyopathy: effects of continuous positive airway pressure. Lancet 1991338:I480-4. Suss M. Spieker C. Wienecke R, et al. Twenty-four-hour blood pressure

prolile in elderly hypertensives: effects of heart failure. J Hypertens 1991;9(suppl6):S338-9. Somers VKi. Mark AL, Abboud FM. Sympathetic activation by hypoxia and hypercapnia-implications for sleep apnea. Clin Exp Hypertens Theory Pratt l!J88;kIO(suppl 1):4&22. Somers VK. Mark AL, Zavala DC. Abhoud FM. Iduence of ventilation and hypocapnia on sympathetic nerve responses to hypoxia in llormal

humans. J Appl Physiol1%~67:2095-108. Somers VK. Mark AL. Zavala DC, Abboud FM. Contrastinn effects of hypoxia and hypercapnia on ventilation and sympathetic activity in humans. J Appl Physiol 1%9;67:210!-6. Hedner J, Ejnell II, Caidahl K. LeI? ventricular bypertrophy ia- dependent of hypertension in patients with obstructive sleep zpnoea. 3 Hypertens 1990;8:941-6. Hedner J. Ejnell H. Sellgren J, Hedner T, Ws*Uin G. Is high and fluctuating muscle nerve sympathetic activity in the sleep apnoea syndrome of pathogenetic importance for the development of hypertension? J Hypertens 1988;6(suppl4):S529-31. Colucci WS, Ribeiro JP, Rocco MB, et al. Impaired chmnotropic response to exercise in patients with congestive heart failure: role of postsynaptic @adrenergic desensitization. Circulation 1989:80:314-23. Mann DL. Kent RL, Parsons B. Cooper G. Adrenergic effects on the biology of the adult mammalian cardiocyt:. Ciiulation 1992;85:7% 804. DiBona GF. Sympathetic neural control of the kidney in hypertension. Hypertension l99l;l9(suppl I):I-28-35. Morali GA, Floras JS, Legauk L. Tobe S, Skorecki KL, Blendis LM. Muscle sympathetic nerve activity and renal responsiveness to atrial aatriuretic factor during the development of hepatic ascites. Ar.r J Med 1991;91:383-92. Folkow B. Cardiovascular structural adaptation: Its role in Ihe titiatiun and maintenance of primary hypertension. Clin Sci Mol Me4 197835: 3!?-22s. Zelis R, Flaim SF. Alterations in vasomotor tone in congestive heart failure. Pmg Cardiovasc Dis 1982:24:437-59.

70. Floras JS. Epineptine and the genesis of hypertension. Hynertension 1992;19:1-18.

71. Yamada Y. Miyajima E. Tochikubo 0. et al. Impaired baroreflex changes in muscle sympathetic nerve activity in adolescents who have a family history of essential hypertension. J Hypertens 1988;6(suppl 4):S525-8.

72. Anderson EA. Siey CA, Lawton WJ, Mark AL. Elevated sympathetic nerve activity in borderline hypertensive humans: evidence horn direct intraneural recordings. Hypertension 1~,14:177-83.

73. Floras JS. Senn B. Absence of postexercise bypotension and sym- pathoinhiiition in normal subjects: additional evidence for increa& sympathetic outllow in borderline byperttnsion. Can J Cardiol 1991;7: 253-e.

74. Floras JS, Legault L. Morali GA, Ham K, Blendis LM. Increased sympathetic outilow in cirrhosis and ascites: direct evidence from . ._ -ml recordings. Ann Intern Med 1991;114:373-80.

75. ykada Y Miyajhna E Tochikubo 0 Matsukawa T. I&ii M. Age- related &a&es in must& sympathetic nkrve activity In essential hypertension. Hypertension 1%9:13:870-7.

76. Gribbin B. Pickering TG. Sleight P, Peto R. The effect of age and high blood pressure on bamrellex sensitivity in man. Circ Res 1971;29:424- 31.

77. Hemiksen JH, Ring-Larsen H. Kanst~p IL, Christensen NJ. Splanch- nit and renal elimination and release of catecholamines in cirrhosk evidence of enhanced sympathetic nervous activity in patients with decompensated cirrhosis. Gut 1~,2531034-43.

78. Warner IX, Campbell PJ, Morali GA, Logan AG. Skorecki KL. Blendis LM. The response of atrial natriuretic factor and sodium excretion to dietary sodium challenges in patients with chronic liver disease. Hepa- tology 1990;12:460-6.

79. Conway J. Hemodynamic aspects of essential hypertension in humans. Physiol Rev 1984;61:617-60.

80. Lund-Johanson P. Twenty-year follow-up of hemodynamics in essential

84A FWRAS SYMPATHETIC ACTIVATION IN HEART FAILURE

JACC Vol. 22. No. 4 (Supplement A) October 1993%A-84A

hypertension duriag rest and exercise. Hypertension 1991;18(suppl q ):m-54-61.

81. Levenson J, Sii AC, Safar ME. Bouthier ID, London GM. Elevation of brachiai arterial blood velocity and volumic flow mediated by peripheral beta-adrcrircceptors in patients with bordedine hypertension. Circuiation !98s;; !:66%8.

82. Kowakdti HJ, Abebnan WH. The cardiac output at rest in Laenaec’s ehbosis. J Clin Invest 1953;32:192%33.

83. Bern&i M, Trevisani F, Santini C, et al. Plasma norepinephrine, weak neumtmnsmitters, and renin activity dur& active tilt@ in liver &rhosis: relationship with cardiovascuiar homeostasis and renal function. Hepatology 1983$56-64.

84. S&tier RW, Arroyo V, Bemardi M, Epstein M, Hemiksen HI, Rodes J. Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cbrhosis. Hepatology 1988$ 1151-7.

85. Schrier RW. Patho8enesis of sodium and water retention in high-output and low-output caulii failure, nephrotic syndrome, cirrhosis, and pregnancy. N Et@ J Med 1988319: 1127-34.

86. Rose CP, Burgess JH, Cousineau D. Tracer notupinephrine kinetics in coronary circulation of patients with heart failure secondary to chronic ~rcssurc and vobune overload. J Clin Invest 1985:76: 1740-7.

87. Meredith IT, Eiseuhofer G, Lambert GW, Dew& EM, Jennings GL. Esler MD. Cardiac svmnathetic nervous activity in connestive heart failure. Evidence for~i&eased neuronai norephtephrine-release and preserved neuronal uptake. Circulation 1993,88:136-U.

88. Valiance P, CoBii J. Moncada S. Effects of endotheliiderived nitric oxide on peripherai arterioh tone in man. Lancet 1989;2:99-1090.

89. Pmua JA. Quyyumi AA, BNSII JB. Epstein SE. Abnonual endothelium- dependent vascular relaxation in patients with essential hypertension. N Et&J Med 199&323:22-7.

90. Kubt~H, Rector TS, Bank Al, WiUiams RE, Heifetx SM. Endothelium- dependent vasodilation is attenuated in patients with heart failure. Circulation 1991$4:15%96.

91. Katz SD, Biiucci L, Sabba C, et al. Impaired endothelium-mediated vasodBatiou in the peripheral vasculature of patients with congestive heart fkibue. J Am Coil Cardiol 1992;19:918-25.

92. Valiance P, Moncada S. Hyperdynamic circulation in cirrhosis: a role for nitric oxide? Lancet 1991;337:776-8.

93. Croxier IO, Nicholls MO, Btram H, Espiner EA, Gometz HJ, Warner NJ. Haemodynamic effects of atrial peptide infusion in heart failure. Lancet lW2: 1242-5.

94.

95.

%.

97.

98.

99.

DiBona GP, Sawin LL. Role of renal nerves in sodium retention of cirrhosis and congestive heart failure. Am J Physioll991;26OR298-305. Cavero PC, Wmaver J. A&us L, Burnett JC. Renal nerves oppose the natriuretic action of alrid natriuretic factor (ANF) in acute experimental congestive heart failure (abstract). Am J Hypertens 1991;4:39A. Cohn JN, Archibald DG, Ziesche S. et al. E&t of vasodilator therapy on mortality in chronic congestive heart failure: results of a Veterans ~~dm&tration Cooperative Study (V-HeFT). N Et@ J Med 1986,314:

Dte CONSENSUS Trial Study Group. ElTects of ensiaptil on mortality m severe ewgestive heatt failtnu: results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Et@ J Med 1987;316:1429-35. The SOLVD Invest@tors. Etfect of enalapril on survival in patients with reduced left venwicular ejection fractions and congestive heart tbilure. N Engl J Med 1991;325:293-302. Cohn JN. Johnson G, Zesche S, et al. Comparison of enalapril with hydralazinc&osorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;3=303-IO.

1tN. The SOLVD Investigators. EFect of enabiprii on mortaiity and the development of heart failure in asymptomatic patients with reduced left ventricular ejection fractions. N Et@ J Med E&2:327:685-91.

101. Benedict CR, Weiner DH, Johnston DE, et al., for the SOLVD Inves- t@ators. Comparative neurohormonal responses in patients with preserved and impaired left ventricular function. Results of the Studies of Left Ventricular Dystimction (SGLVD) Registry. J Am Coll Cardiol 1993p(suppl A):l46&53A.

192. Yang T. Levy MN. Sequence of excitation as a factor in sympathetic- parasympathetic interactions in the heart. Circ Res 1992,71:898-905.

103. Clarke J, Beq@in N. Larkin S, Webb D. Maseri A, Davies G. Intemction of neuropeptide Y and the sympathetic nervous system in vascular control in man. Ciiulation 1991$3:774-7.

104. Franciosa JA. Schwartz DE. Acute hemodynamic elfects ofnorepineph- tine inhibition in patients with severe chronic congestive heart failure. J Am Coli Catdiol 1989#624-30.

105. Feguson DW. Abboud FM, Mark AL. Selective impairment of barore Sex-mediated vasoconsttictor responses in patients with ventricular dysfunction. Circulation 1984@451-60.

106. Maria-Net0 JA, Pmtya AO, Galio L, Maciel BC. Abnormai baroreflex control of heart rate in decompensated congestive heart failure and reversal after compensation. Am J Cardiol 1991;67:604-IO.

107. Grima EA. Moe GW, Howard RJ, Armstrong PW. Recovery of baroreilex sensitivity in experimental heart failure (abstract). Circulation 199l;&l(suppl II):II-554.

108. Ellenbogen KA, Mohanty PK, Sxentpetery S, Thames MD. Arterial baroretlex abnormalities in heart failure: reversal after orthotopic cardiac transplantation. Ciilation 1989;79:51-8.

169. Coats A. Adamopouios S, Radaelii A, et al. Controlled trial of physical training in chronic heart failure: exercise performance, hemodynamics, ventilation, and autonomic function. Circulation 1992$5:2119-31.

110. Floras JS. Sympathoinhibitory effects of at&i natriuretic factor in normal humans. Circulation 1990;81:1860-73.

111. Holtz J, Mtmzel T, Sommer 0. Bassenge E. Sympathoadmnai inhibition by atrial natriuretic peptide is not attenuated during development of cotutestive heart failure in dg. Circulation 1989;80:1862-9.

112. Chapleau MW. Hqidttcxok G, Abboud FM. Peripheral and central mechanisms of baroreilex resetting. Clin Exper Pharm Physiol 1989; I5(suppl):31-43.

113. Ferguson DW. Berg WJ. Sanders JJ, Roach PJ, Kempf JS. Kienzie MG. Sympathoinhibitory responses to digitalis glycosides in heart failure patients: direct evidence from sympathetic neural recordlq. Ciiuia- tion 1989$0:65-77.

114. Goldsmith SR, Simon AB, Miller E. Effect of d@lis on norepktephrine kinetics in cotgestive heart failure. J Am Coli Cardio11992;~0:858-63.

115. Osterxiel KS, Ruhrig N. Dietx R, Manthey J, He&t J. Kubler W. InUuence ofcnptopril on the atteriai baroreceptor retlex in patients with heart failure. Eur Heart J 1988,9:1137-45.

116. Goldsmith SR, Simon AB. The effect of angiotensin converting enzyme inhiiition on norepinephrine kinetics in congestive heart failure (ab- stractk Ciinlation 1991$4(supp~ II):Il-742.

117. Packer M. The development of positive inotropic agents for chronic hetzt hrikne: how have we gone astray? J Am Colt CardiilB~93;22(suppl A): 119A-26A.

118. Wallin BG, Sundlof G. Sttmngmn E, Aberg H. Sympathetic outtlow to _ muscles during treatment of hypertension with metopmlol. Hyperten- sion 19U4D55%2.

119. Bristow MR, Olson S. Gilbert EM, et al. B_blockade with carvedilol selectively lowers cardiac adrenergic drive in the failing human heart (abstract). J Am CoU Cardiol 1992;19:146A.

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