the sympathetic nervous system in chronic heart failure

The Sympathetic Nervous System in Chronic Heart Failure

J a c o b J o s e p h a n d E d w a r d M i c h a e l G i l b e r t

The sympathetic nervous system plays a pivotal role in the natural history of chronic heart failure (CHF). There is early activation of cardiac adrenergic drive, which is followed by an increasing magnitude of generalized sympathetic activation, with worsening heart failure. The adverse consequences predomi- nate over the short-term compensatory effects and a r e mediated through downregulation of 13-receptor function and harmful biological effects on the cardiomyocyte, p-blockers exert a beneficial effect on the natural history of CHF by attenuating the negative biological effects, restoring homogeneity of contractile/relaxant mechanisms, and reducing the risk of myocardial ischemia and arrhythmias. After pioneering work conducted over 20 years ago, numerous studies have shown the beneficial effects of IS-blockade on left ventricular function, and survival, morbidity, and mortality rates in CHR Large-scale trials are underway to determine the overall benefits of p-blockade in heart failure. Copyright © 1998 by W.B. Saunders Company

T he clinical syndrome of heart failure is a continuum of complex interactions between

myocardial dysfunction and ensuing neurohormonal activation. Primary myocardial dysfunction, systolic and/or diastolic, initiates a set of pathophysiological responses that compensate for the initial hemodynamic insult but subsequently exert long-term deleterious effects on the heart, leading to chronic heart failure (CHF). Exciting developments over the last decade have clearly implicated neuroendocrine mechanisms in the progression of heart failure, especially the sympathetic nervous system and the renin-angiotensin- aldosterone system.

The plasma norepinephrine level, which has been found to be a sensitive indicator of sympathetic nervous system activity, 1 is elevated in CHE In a substudy of the Studies of Left Ventricular Dysfunction group, baseline plasma norepineph-

rine levels were found to be significantly raised in patients with asymptomatic left ventricular dysfunction, with a further significant increase in levels in patients with overt heart failure. 2 Similar results have been observed by Remme et al, 3 indicating a strong relation between the extent of sympathetic activation and disease progression.

Sympathetic activation correlates with mortality in CHE Swedberg et al found that in patients with severe heart failure who were randomized to receive enalapril or placebo, there was a strong positive relation between mortality and norepinephrine levels in the placebo group. 4 Other investigators have also found a correlation between high plasma norepinephrine levels and adverse prognosis. 5-r

These studies clearly underscore the impor- tance of sympathetic activation as a marker of adverse interaction of the organism with the cardiovascular system. This review examines the role of the sympathetic nervous system in the pathogenesis and progression of CHF, with spe- cial reference to the cardiac adrenergic nervous system.

Activation of the Sympathetic Nervous System

Preferential activation of the cardiorenal sympathetic axis has been shown in heart failure. 8,9 In a

From the Division of Cardiology, University of Arkansas for Medical Sciences, Little Rock, AR, and the Division of Cardiology, University of Utah Health Sciences Center, Salt Lake City, UT.

Address reprint requests to Edward Michael Gilbert, MD, Associate Professor of Medicine, Director, Heart Failure Treatment Program, Division of Cardiology, University of Utah Health Sciences Center, 50 N Medical Dr, Salt Lake City, UT 84132.

Copyright © 1998 by W.B. Saunders Company 0033-0620/98/4101-100258.00/0

Progress in Cardiovascular Diseases, Vol. 41, No. 1, Suppl. 1 (July/August), 1998: pp 9-16 9

10 JOSEPH AND GILBERT

study of the plasma kinetics of norepinephrine in the normal population and patients with heart failure, cardiac and renal norepinephrine spillover were markedly increased in patients with heart failure, whereas spillover from the lungs remained normal, s Rundquist et aU ° showed that increased cardiac adrenergic drive occurs early in heart failure, before an increase in total body or renal sympathetic activation. This preceded a generalized activation of the sympathetic nervous system, with an advancing degree of heart failure.

The precise mechanism involved in activation of the sympathetic nervous system is not yet completely defined. Normal reflex mechanisms serve to detect and rectify changes in cardiac performance. Afferent signals from the cardiac chambers and great vessels, when stimulated, inhibit the cardiovascular centers in the brain, resulting in reduced sympathetic outflow from the central nervous system. A decrease in cardiac output or blood pressure leads to a decrement in inhibitory signals from these sensory receptors to the cardiovascular control centers, which lead to increased sympathetic outflow and release of vasopressin. These compensate for the hemodynamic abnormality by increasing blood pressure and intravascular volume. A decrease in cardiac output is the best correlate of myocardial adrenergic activation and is independent of left ventricular pressure or volume overload, as was shown in a study of heart failure patients with mitral stenosis.II

However, the expected close correlation between the degree of sympathetic activation and hemodynamic derangement does not exist because circulating norepinephrine levels do not correlate well with the severity of indices of hemodynamic derangement. 12 Marked interindi- vidual variation of sympathetic activation exists, with one third of patients with severe CHF showing normal levels of plasma norepineph- rineJ 2 These findings indicate that enhanced sympathetic activation in CHF is not a simple, predictable reflex phenomenon.

Abnormal baroreceptor function is implicated in the sympathetic hyperactivity of CHF by baroreceptor dysfunction in experimental and human heart failure. 13 This leads to an impairment in the ability of cardiac and arterial baroreceptors to suppress sympathetic activity and to release vasopressin from the central nervous system. Left

atrial baroreceptors show attenuated responses to increases in atrial pressures after volume expan- sion. These abnormalities may be related to changes in arterial compliance or fragmentation of atrial receptor endings.

Effects of Generalized Sympathetic Stimulation

Abnormal activation of the sympathetic nervous system leads to a wide range of pathophysiological changes in patients with CHE In the early stages of CHF it plays a compensatory role, supporting the failing heart by increasing heart rate and myocardial contractility. Arteriolar vasoconstriction maintains blood pressure and vital organ perfusion, whereas venoconstriction aug- ments venous return and cardiac filling pressures and invokes the Frank-Starling mechanism. Dia- stolic ventricular function is also enhanced by adrenergic stimulation via ~3-receptor-mediated increases in cyclic adenosine monophosphate, with subsequent phosphorylation of troponin I, phospholamban, and the calcium pump. This leads to reduced myofilament calcium sensitivity, accelerated sequestration of calcium into the sarcoplasmic reticulum, and increased removal of sarcoplasmic calcium. 14,x5

These compensatory effects are eventually out- weighed by a number of adverse effects that serve to exacerbate the CHF syndrome. This shift to deleterious consequences may be the result of disproportionate activation of the sympathetic nervous system, either in magnitude or duration.

The increase in cardiac work and oxygen consumption imposed by a higher afterload results in an increased burden to the diseased heart. Coronary blood flow may be reduced through coronary vasoconstriction or shortening of the diastolic phase. Diastolic wall stress is markedly increased by the compensatory increase in end diastolic volume. Interaction of the sympathetic nervous system with other endocrine systems also contributes to create an unfavorable milieu for the failing heart. Sympathetic stimulation of renin secretion leads to aldosterone production, resulting in salt and water retention. Increased renin activity also leads to increased production of the powerful vasoconstrictor, angiotensin II. These changes lead to increased systolic and diastolic wall stress. Production of another power-

ADRENERGIC DRIVE IN HEART FAILURE 11

ful vasoconstrictor, endothelin-1, is also enhanced by catecholamines, further contributing to increased peripheral resistance in heart failure.

Sympathetic activation also leads to structural alterations in the heart. Stimulation of oq- receptors leads to myocardial hypertrophy. 16 Ex- posure to excessive catecholamines can be toxic to the myocardium, causing contraction band lesions and myocyte necrosis3 7,18 The cause of such damage is unclear, but free-radical genera- tion and calcium overload have been implicated. 19

The toxic effects of norepinephrine on myo- cytes can be shown in isolated cell culture. The magnitude of cell death is concentration dependent. 2° Concentrations of norepinephrine observed in patients with end-stage heart failure have been shown to produce cell necrosis in tissue culture. In these models, the addition of both ~- and o~-adrenergic antagonists to the culture medium blocks the toxic effects of norepinephrine. Adrenoreceptor downregulation is another major outcome of chronic exposure to excess norepinephrine, and is discussed in detail in the next section. Hence, sympathetic activation creates a vicious cycle of worsening cardiac performance leading to its further activation.

Cardiac Sympathetic Activity in Heart Failure

Studies in the 1960s showed depletion of cardiac norepinephrine stores in CH E 21'22 This was thought to be caused by a reduction in synthesis 23 or was secondary to a decrease in the number of normal nerve endings. 24 However, increased cardiac norepinephrine turnover is now known to be a feature of heart failure, 25 in keeping with the observation of increased cardiac adrenergic drive early in heart failure. 10

Recent studies have shown the operative mechanisms whereby an increased cardiac adrenergic drive is maintained in the presence of depleted cardiac norepinephrine stores. Eisenhofer et a126 conducted a study in patients with and without heart failure in which the investigators measured norepinephrine kinetics and metabolism. The results showed that there was an increased neuronal release of norepinephrine but a decreased efficiency of neuronal reuptake, resulting in an increased availability of norepinephrine for recep-

tot binding. However, the chronically increased turnover with inadequate reuptake and storage led to a reduction of norepinephrine stores in heart failure by about 50%. In contrast with earlier studies, norepinephrine production was not found to be reduced as indicated by adequate capacity for tyrosine hydroxylation, the rate- limiting step in norepinephrine synthesis. Car- diac fractional extraction of tritiated norepinephrine is reduced in patients with mild-to-moderate heart failure, implicating impaired neuronal reuptake as a major abnormality of cardiac sympathetic function in heart failure.l° This was corrobo- rated by investigators at the author's institution in patients with idiopathic cardiomyopathy. 27 Thus, the increased adrenergic drive in the failing heart is maintained by these mechanisms, leading to an increased rate of norepinephrine spillover from the heart in spite of depletion of norepinephrine stores.

Adrenergic hyperactivity in the heart may lead to destruction of sympathetic nerve terminals, and prolonged stimulation may exhaust neuronal energy stores in addition to neurotransmitters. 28 Sympathetic stimulation in experimental animals has been shown to deplete norepinephrine, while at the same time increasing dopamine stores in adrenergic nerve terminals, z9,3° Neuronal dopamine may be susceptible to oxidation with resultant accumulation of 6-hydroxydopamine, a powerful neurotoxin.Z8

Neuronal loss, resulting from interplay of the above factors, is not spread uniformly across the failing myocardium. Animal models and studies in humans show heterogeneity of norepinephrine loss. 31,32 Both richly innervated and markedly denervated areas are seen in the myocardium of the failing heart. In animal models, areas border- ing connective tissue scars and perivascular zones have normal or increased innervation, whereas other myocyte areas are totally depleted of nerve endings. 31 This heterogeneity of sympathetic activation has pathophysiological significance. The lack of temporal coordination of cardiac contraction and relaxation across the myocardium can lead to deterioration in cardiac performance. 33 This may also contribute to the marked heterogeneity of resting potentials and action potential duration seen in animal models of heart failure. 34,35 This combined with the structural heterogeneity that creates a conducive environment for


re-entrant circuits and the increased triggered activity 36 probably leads to the increased risk of sudden death seen in CHF patients. Hypokalemia induced by [32-stimulation, especially in the setting of diuretic therapy, may also play a role. 3r

Adrenergic Receptor Function in the Failing Heart

The/3-adrenergic receptor pathway predominates in the human heart, as evidenced by the low density of %-receptors in the ventricular myocardium. 38,39 Studies in human hearts have identified the variations in [3-receptor subpopulations in heart failure. 4° The [31:[32 ratio decreased from 77:23 in the nonfailing ventricle to 60:38 in the failing ventricle; this resulted in a 62% selective decrease in the [31-receptor population, with mini- mal change in [32-receptors. The [31 component of the inotropic response to adrenergic stimulation is markedly decreased in heart failure, with a compensatory increase in the ~2 component.

The molecular basis of agonist-induced [3-adrenergic receptor downregulation may be related to RNA binding proteins that selectively bind to [31- and [32-receptor messenger RNAs (mRNAs) spar- ing %b-adrenergic receptor mRNA. 41,42 These proteins were found to be induced by agonists that downregulate [3-receptor mRNA. The mRNA- binding protein, AUF 1, which decreases the stabil- ity of mRNA, binds to the A + U-rich elements in the 3'-untranslated regions of many mRNAs, including that of [3-receptor RNA. In patients with heart failure, expression of AUF1 is upregu- lated and associated with a significant decrease in mRNA for the [31-adrenergic receptor and subsequent downregulation of the receptor. 43

The ~2-receptor system undergoes uncoupling in the failing human heart, with retained num- bers. Adenylate cyclase stimulation by the selective [32-agonist zinterol is decreased by approxi- mately 30% in the failing human heart# 4 Other abnormalities of [3-receptor function are the uncoupling of ~-receptors 45 and the upregulation of [3-adrenergic receptor kinase, 46 with resultant phosphorylation of [3-receptors, 4r,48 increased activity or amount of inhibitory G-protein, 49,5° and decreased adenylate cyclase activity? 5,51

a~-receptor density is not changed or only slightly increased in heart failure. 38,52 Hence, this pathway may not play a major role in supporting

the contractile function of the failing heart. How- ever, %-receptor systems have been shown to influence myocyte growth, and therefore may stimulate cardiac hypertrophy in the failing heart. 16,53

Progressive downregulation of [3-adrenergic receptors in heart failure correlates with the clinical features observed in the CHF syndrome. Assess- ment of [3-receptor density in endomyocardial biopsy specimens of patients with CHF showed a progressive decrease in receptor density with increasing severity of heart failure. 54 The decrease in receptor density correlated with a decrease in responsiveness to dobutamine with preserved response to calcium, indicating impairment of [3-agonist-mediated contractile response. There is also a decrease in contractile response to indi- rectly acting [3-agonists such as dopamine, which acts by promoting release of neuronal norepinephrine because cardiac norepinephrine stores are depleted in heart failure) 5 Maximal exercise oxygen consumption in CHF patients also correlates with endomyocardial-biopsy [3-receptor density, implicating [3-receptor downregulation in the reduced chronotropic and inotropic responses to peak exercise in heart failure. 56

Drugs producing favorable effects in CHF alter cardiac adrenergic function. Angiotensin-convert- ing enzyme inhibitors lower cardiac adrenergic drive and increase [3-receptor density in heart failure patients with an increased cardiac adrenergic drive at basel ines

The effects of the selective [31-blocker metoprolol have been compared with carvedilol (a nonse- lective [3-blocker and cq-selective agent) in two concurrent placebo-controlled trials. 58 Carvedilol lowered cardiac adrenergic drive but caused no change in [~-receptor expression in the heart. Metoprolol did not lower cardiac adrenergic activity and actually increased central venous norepinephrine levels and [3-receptor density in the heart. Although there were no significant differences in hemodynamic effects between the two drugs, carvedilol produced relatively greater im- provements in indices of left ventricular function.

Sympathetic Blockade in Heart Failure

The differential effects on cardiac adrenergic drive and [3-receptor density produced by beneficial

ADRENERGIC DRIVE IN HEART FAILURE 13

therapies in CHF raises the interesting question: Is it beneficial to upregulate [g-receptor function in heart failure? The clinical symptoms of heart failure and the progressive decline in myocardial function can be explained by the two general adverse consequences of increased cardiac adrenergic activity. First, the downregulation of ~-recep- tot signal transduction mechanisms leads to decreases in myocardial reserve and impaired exercise capacity, a hallmark of cardiac failure. Second, the adverse biological consequences on the cardiomyocyte mediated via the remaining intact signal transduction mechanisms in the setting of increased cardiac adrenergic drive lead to a progressive decline in cardiac function. 59 Consequently, elimination of the excess cardiac adrenergic drive would have beneficial effects on the natural history of progressive CHF, although exercise function may be positively influenced by the enhanced [3-agonist responses associated with increased density of ~-adrenergic receptors. The elimination of temporal heterogeneity of sympathetic activity in the heart would also have significant beneficial effects in improving contractile function and decreasing arrhythmogenicity. A decrease in heart rate may shift the heart to a flatter portion of the restitution curve, improving contractile function. ~-blockade may also prevent ischemic episodes by reducing the imbalance between oxygen supply and demand.

The pioneering investigations of Waagstein et al conducted over 20 years ago indicated the beneficial effects of [~-blockade in heart failure caused by dilated cardiomyopathy. 6° Small studies subsequently showed that [~-blockers improve systolic function, 61,62 reduce ventricular arrhythmias, 63 and exert antifibrillatory effects. 64 Benefi- cial effects may also be accrued by attenuation of other neuroendocrine responses, especially of the renin-angiotensin system. The Metoprolol in Di- lated Cardiomyopathy study showed a 34% reduction in heart failure progression, defined as need for transplantation, or death in nonischemic cardiomyopathy patients treated with metoprolol. 65 However, the Cardiac Insufficiency Bisoprolol Study (CIBIS) failed to show any beneficial effect on mortality in patients with heart failure in the New York Heart Association (NYHA) functional classes III and IV 66 The pooled results of the

United States Carvedilol Heart Failure Study Group trials of carvedilol in mild-to-severe heart failure showed an overall significant decrease in the mortality rate. er The Australia/New Zealand Heart Failure Trials in patients with mild-to- moderate heart failure in ischemic cardiomyopathy showed a trend toward reduced mortality rates and a significant decrease in combined events of death and hospitalization. 6s

Presently, three large trials are underway to assess the effect of ~-blockade in reducing the mortality rate in heart failure. In the Beta-blocker Evaluation Survival Trial, 69 2,800 patients were randomized to receive either bucindolol or placebo in addition to standard therapy for CHF, and it is expected that there will be a 4.5-year fol- low-up (primary endpoint is total mortality). A starting dose of 3 mg bucindolol was titrated over 6 or more weeks to a final dose of 100 or 200 mg/day. CIBIS II, 7° which was terminated in early 1998 because of a positive effect on survival, is expected to report in late summer 1998. This trial randomized 2,500 patients to receive either bisoprolol or placebo in addition to standard therapy. The primary endpoint was to evaluate the effect of bisoprolol 1.25 to 10 mg daily on long-term (>2.5 years) all-cause mortality rates in patients with symptomatic CHE Both these trials were restricted to NYHA class III and IV patients. The Carvedilol Prospective Randomized Cumulative Survival Trial, a worldwide study of 1,800 patients with severe CHF related to ischemic or nonischemic disease, will have mortality rate as its primary endpoint.71 Patients will receive carvedilol or placebo in addition to standard therapy, and they will be followed up until 900 total deaths have occurred,

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1 6 JOSEPH AND GILBERT

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the sympathetic nervous system in chronic heart failure

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