BASIC SCIENCE
Sympatholysis and cardiac sympathetic nerve function in the treatment of congestive heart failure*
Chang-seng Liang, MD, PhD, FACC*,*
* Department of Medicine (Cardiology Unit), University of Rochester Medical Center, Rochester, New York, USA
* Reprint requests and correspondence: Dr. Chang-seng Liang, University of Rochester Medical Center, Cardiology Unit, Box 679, 601 Elmwood Avenue, Rochester, New York 14642, USA.
chang-seng_liang{at}urmc.rochester.edu
Activation of the sympathetic nervous system, manifested by an increase in plasma norepinephrine (NE), is a salient feature in congestive heart failure (HF). This was first thought to be an important adaptive mechanism to support the failing myocardium (1). However, evidence now indicates that activation of the sympathetic nervous system is detrimental and maladaptive. Long-term exposure of the heart to NE can cause not only myocardial ß-adrenoceptor down-regulation but also cardiac hypertrophy, ischemia, cardiac arrhythmia, tissue necrosis, and myocyte apoptosis, all of which have been shown in patients with congestive HF (2). This concept is further supported by several large clinical trials showing that long-term ß-blocker therapy can not only improve left ventricular (LV) systolic function but also increase survival in patients with chronic HF secondary to LV systolic dysfunction (3–5).
Given the overwhelming success of the ß-adrenoceptor blocker therapy, several investigators have looked into the possibility that more effective therapy can be derived by silencing the sympathetic nervous system activity with sympatholytic agents such as moxonidine and clonidine. Unlike clonidine, which acts on the central  -2 adrenergic receptors, moxonidine preferentially stimulates the brain stem imidazoline-1 receptor to decrease sympathetic outflow (6). Although both agents have been shown to reduce plasma NE and produce some benefits in patients with HF (7–9), the long-term Moxonidine Congestive Heart Failure (MOXCON) trial was terminated prematurely because of increased mortality in the moxonidine group (10). Similarly, a subgroup analysis of the Beta Blocker Evaluation of Survival Trial (BEST) showed that those subjects who died during the study had higher plasma NE concentration at baseline and greater reductions of plasma NE after three months of bucindolol treatment than subjects who survived (11). It was speculated that bucindolol has an effect on the central nervous system that suppresses the sympathetic outflow (11). The authors conclude that sympatholytic agents should be given with caution to patients with severely compromised hemodynamics in whom a critical minimal adrenergic tone is important. The findings suggest that the sympathetic nervous system activation can be both adaptive and maladaptive, depending on the degree of basal sympathetic activation and the extent of sympatholysis.
In this issue of the Journal, Igawa et al. (12) report a study in which three doses of guanethidine were used to produce dose-dependent decreases of plasma NE in rats with HF after myocardial infarction. Guanethidine was started two days before coronary occlusion and continued for 28 days after myocardial infarction. All three doses of guanethidine improved the short-term survival after coronary artery occlusion, but only the low-dose guanethidine (1 mg/kg/day) reduced LV dilation and improved LV mechanical function and survival over 28 days. When the high dose of guanethidine (10 mg/kg/day) was administered, only three of 34 rats survived four weeks. An intermediate dose of guanethidine produced no beneficial effects on either cardiac hemodynamics or four-week mortality compared with the control group. Results of the study indicate that the effects of sympatholytic agents are dose-dependent and that excessive sympathetic inhibition may be deleterious in HF.
However, unlike bucindolol in the BEST study, long-term use of carvedilol reduced cardiovascular mortality and morbidity in patients with very severe HF in whom removal of the noradrenergic drive by ß-receptor blockade was expected to exert a negative effect (13). Thus fundamental differences may exist between sympatholysis and ß-receptor blockade in their delivery of an anti-adrenergic effect. Furthermore, unlike moxonidine and bucindolol, guanethidine acts on the peripheral sympathetic nerves to reduce NE release. Ultrastructural and immunohistologic changes such as those produced by immune-mediated neuronal degeneration have been shown to occur in the peripheral sympathetic nerves after guanethidine treatment (14,15). This raises a question whether the harmful effects of guanethidine reported in the study by Igawa et al. (12) were related to destruction of the cardiac sympathetic nerves.
Recently, radio-iodinated metaiodobenzylguanidine (123I-MIBG), a structural analogue of NE, has been used to study the integrity and function of the cardiac sympathetic nervous system (16). The failing heart is characterized by reduced washout and distribution of MIBG on myocardial scintigraphy. Studies have shown that cardiac sympathetic nerve innervation as demonstrated by MIBG scintigraphy is an independent predictor for fatal outcomes in patients with HF (17). More importantly, the beneficial effects of carvedilol (18), metoprolol (19), spironolactone (20), and enalapril (21) are associated with improvements in cardiac sympathetic innervation. In contrast, bucindolol therapy, which showed only marginal survival benefits (22), did not improve the sympathetic nerve function as measured by MIBG (23).
Our laboratories have studied the pre- and post-synaptic changes of the cardiac sympathetic nerve function in experimental HF. We were the first to demonstrate a chamber-specific reduction of myocardial ß-receptors, occurring only in the failing right ventricle of dogs with right-heart failure produced by tricuspid avulsion and progressive pulmonary artery constriction (24). The decrease of myocardial ß-adrenoceptor density is linked to reduced NE uptake activity, NE uptake-1 carrier density (25,26), and increased interstitial NE (27). Furthermore, because myocardial NE uptake is also reduced by exogenous NE administration, we speculate that the changes of the sympathetic nerve terminal function in HF are caused by the increased interstitial NE concentration (27). The functional importance of the NE uptake site was further studied in rabbits at various time intervals after the start of rapid ventricular pacing (28). We found that rapid ventricular pacing caused early sympathetic nervous system activation, followed in sequence by reduced myocardial NE uptake, loss of neuronal NE, and down-regulation of myocardial ß-adrenoceptors. In addition, long-term use exogenous NE has been shown to reduce myocardial NE uptake and ß-adrenoceptor receptor density in normal animals without HF (29). The interdependence of increased sympathetic stimulation, decreased cardiac NE uptake, and myocardial ß-adrenoceptor down-regulation is further borne out by a recent study by Leineweber et al. (30), who found that neurohumoral activation is essential for the reduction of myocardial ß-receptors in the hypertrophied right ventricle produced by monocrotaline, which, similar to our earlier studies in right-heart failure (24,25), is characterized by a chamber-specific reduction of myocardial NE uptake sites (31).
The functional importance of the NE reuptake mechanism in the regulation of myocardial ß-receptor density and post-synaptic ß-adrenergic inotropic responsiveness was further studied in the right-heart-failure animals treated with desipramine (32). Unlike guanethidine, desipramine blocks neuronal uptake of NE at the sympathetic nerve terminals without destroying sympathetic nerves. We found that desipramine facilitated the reduction of myocardial ß-adrenoceptor density and ß-adrenergic subsensitivity in the animals. In contrast, selegiline, which is a central 2-agonist with a neuroprotective effect, attenuated the increase in plasma NE and the decrease of myocardial ß-receptor density and improved cardiac mechanical function in pacing-induced cardiomyopathy (33). Selegiline also prevented the reductions of NE uptake activity, NE uptake-1 carrier site density, and sympathetic neurotransmitter profiles in the failing heart.
Our studies suggest a revised paradigm for the treatment of congestive HF. While interventions should be directed toward minimizing the noradrenergic release of NE or blocking the harmful apoptotic and oxidative effects of NE on the sympathetic nerves and cardiomyocytes in HF, attention should be paid to preserving the integrity and NE reuptake function of the sympathetic nerve terminals. Guanethidine produces marked inhibition of the sympathetic nerve activity and plasma NE, but at high doses it also exerts a negative effect on the functional integrity of the sympathetic nerve terminals. Cardiac interstitial NE may have increased further and contributed to the clinical adverse effects of guanethidine (12). Whether moxonidine affects NE uptake or storage in the sympathetic nerve terminals is not known. In addition to selegiline, guanabenz—also an 2-agonist—has been shown to improve cardiac sympathetic NE and tyrosine hydroxylase activity in animals with aortic constriction (34). At least three different presynaptic 2 receptors have been identified and shown to control NE release in HF at present. Brede et al. (35) reported recently that progression of HF produced by aortic constriction was worsened in gene-targeted mice lacking either an 2A or an 2C receptor subtype but not in mice lacking the 2B receptor subtype. It is clear that much remains to be learned about how the 2 receptor–mediated events affect the progression of HF and about whether novel sympatholytic agents can be developed to reduce the noradrenergic drive while preserving the integrity of the sympathetic nerve terminal function.
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Footnotes
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The work was supported in part by U.S. Public Health Service Grants HL-35194 and HL-68151.
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
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References
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1. Chidsey CA, Harrison DC, Brunwald E. Augmentation of the plasma norepinephrine response to exercise in patients with congestive heart failure. N Engl J Med. 1962;267:650–654[Medline]
2. Bristow MR. ß-Adrenergic receptor blockade in chronic heart failure. Circulation. 2000;101:558–569[Free Full Text]
3. Packer M, Bristow MR, Cohn JN, et al. The effect of carvedilol on morbidity and mortality in patients with chronic heart failure. N Engl J Med. 1996;334:1349–1355[Abstract/Free Full Text]
4. The Cardiac Insufficiency Bisoprolol Study (CIBIS-II): a randomized trial. Lancet 1999;353:9–13
5. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Chronic Heart Failure (MERIT-HF). Lancet. 1999;353:2001–2007[CrossRef][Medline]
6. Ziegler D, Haxhiu MA, Kaan EC, Papp JG, Ernsberger P. Pharmacology of moxonidine: an I1-imidazoline receptor agonist. J Cardiovasc Pharmacol. 1996;27(Suppl 3):S26–S37[CrossRef]
7. Dickstein K, Manhenke C, Aarsland T, Køff U, McNay J, Wiltse C. Acute hemodynamic and neurohumoral effects of moxonidine in congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol. 1999;83:1638–1644[CrossRef][Medline]
8. Swedberg K, Bristow MR, Cohn JN, et al. for the Moxonidine Safety and Efficacy (MOXSE) investigators. Effects of sustained-release moxonidine, an imidazoline agonist, on plasma norepinephrine in patients with chronic heart failure. Circulation. 2002;105:1797–1803[Abstract/Free Full Text]
9. Azevedo ER, Newton GE, Parker JD. Cardiac and systemic sympathetic activity in response to clonidine in human heart failure. J Am Coll Cardiol. 1999;33:186–191[Abstract/Free Full Text]
10. Coats AJ. Heart Failure 99: the MOXCON story. Int J Cardiol. 1999;71:109–111[CrossRef][Medline]
11. Bristow M, Krause-Steinrauf H, Abraham WT, et al. Sympatholytic effect of bucindolol adversely affected survival, and was disproportionately observed in the class IV subgroup of BEST. Circulation. 2001;104(Suppl II):II755 (abstr)
12. Igawa A, Nozawa T, Fujii N, Kato B-i, Asanoi H, Inoue H. Long-term treatment of low-dose, but not high-dose, guanethidine improves ventricular function and survival of rats with heart failure after myocardial infarction. J Am Coll Cardiol 2003;42:541–8
13. Packer M, Coats AJS, Fowler MB, et al. for the Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failur. N Engl J Med. 2001;344:1649–1658
14. Schmidt RF, Summerfield AL, Hickey WF. Ultrastructural and immunohistologic characterization of guanethidine-induced destruction of peripheral sympathetic neurons. J Neuropathol Exp Neurol. 1990;49:150–167[Medline]
15. Hougen HP, Thygesen P, Christensen HB, Rygaard J, Svendsen O, Juul P. Effect of immunosuppressive agents on the guanethidine-induced sympathectomy in athymic and euthymic rats. Int J Immunopharmacol. 1992;14:1113–1123[CrossRef][Medline]
16. Henderson EB, Kahn JK, Corbett JR, et al. Abnormal I-123 metaiodobenzylguanidine myocardial washout and distribution may reflect myocardial adrenergic derangement in patients with congestive cardiomyopathy. Circulation. 1988;78:1192–1199[Abstract/Free Full Text]
17. Merlet P, Benvenuti C, Moyse D, et al. Prognostic value of MIBG imaging in idiopathic dilated cardiomyopathy. J Nucl Med. 1999;40:917–923[Abstract/Free Full Text]
18. Lotze U, Kaepplinger S, Kober A, Richartz BM, Gottschild D, Figulla HR. Recovery of the cardiac adrenergic nervous system after long-term beta-blocker therapy in idiopathic dilated cardiomyopathy: assessment by increase in myocardial 123I-metaiodobenzylguanidine uptake. J Nucl Med. 2001;42:49–54[Abstract/Free Full Text]
19. de Milliano PAR, de Groot AC, Tijssen JGP, van Eck-Smit BLF, Van Zwieten PA, Lie KI. Beneficial effects of metoprolol on myocardial sympathetic function: evidence from a randomized, placebo-controlled study in patients with congestive heart failure. Am Heart J. 2002;144:E3[CrossRef][Medline]
20. Kasama S, Toyama T, Kumakura H, et al. Spironolactone improves cardiac sympathetic nerve activity and symptoms in patients with congestive heart failure. J Nucl Med. 2002;43:1279–1285[Abstract/Free Full Text]
21. Somsen GA, van Vlies B, de Miliano PA, et al. Increased myocardial[123I]-metaiodobenzylguanidine uptake after enalapril treatment in patients with chronic heart failure. Heart. 1996;76:218–222[Abstract/Free Full Text]
22. The Beta-Blocker Evaluation of Survival Trial investigators. A trial of the beta-blocker bucindolol in patients with advanced chronic heart failure. N Engl J Med. 2001;344:1659–1667[Abstract/Free Full Text]
23. Eichhorn EJ, McGhie AL, Bedotto JB, et al. Effects of bucindolol on neurohormonal activation in congestive heart failure. Am J Cardiol. 1991;67:67–73[CrossRef][Medline]
24. Fan THM, Liang C-s, Kawashima S, Banerjee SP. Alterations in cardiac ß-adrenergic receptor responsiveness and adenylate cyclase system by congestive heart failure in dogs. Eur J Pharmacol. 1987;140:123–132[CrossRef][Medline]
25. Liang C-s, Fan THM, Sullebarger JT, Sakamoto S. Decreased adrenergic neuronal uptake activity in experimental right heart failure: a chamber-specific contributor to beta-adrenoceptor down-regulation. J Clin Invest. 1989;84:1267–1275[Medline]
26. Himura Y, Felten SY, Kashiki M, Lewandowski TJ, Delehanty JM, Liang C-s. Cardiac noradrenergic nerve terminal abnormalities in dogs with experimental congestive heart failure. Circulation. 1993;88:1299–1309[Abstract/Free Full Text]
27. Delehanty JM, Himura Y, Elam H, Hood WB Jr, Liang C-s. ß-Adrenoceptor downregulation in pacing-induced heart failure is associated with increased interstitial NE content. Am J Physiol Heart Circ Physiol. 1994;266:H930–H935[Abstract/Free Full Text]
28. Kawai H, Mohan A, Hagen J, et al. Alterations in cardiac adrenergic terminal function and ß-adrenoceptor density in pacing-induced heart failure. Am J Physiol Heart Circ Physiol. 2000;278:H1708–H1716[Abstract/Free Full Text]
29. Dong E, Yatani A, Mohan A, Liang C-s. Myocardial ß-adrenoceptor down-regulation by norepinephrine is linked to reduced norepinephrine uptake activity. Eur J Pharmacol. 1999;384:17–24[CrossRef][Medline]
30. Leineweber K, Brandt K, Wludyka B, et al. Ventricular hypertrophy plus neurohumoral activation is necessary to alter the cardiac ß-adrenoceptor system in experimental heart failure. Circ Res. 2002;91:1056–1062[Abstract/Free Full Text]
31. Leineweber K, Seyfarth T, Broddie OE. Chamber-specific alterations of noradrenaline uptake (uptake1) in right ventricles of monocrotaline-treated rats. Br J Pharmacol. 2000;131:1438–1444[CrossRef][Medline]
32. Liang C-s, Himura H, Kashiki M, Stevens SY. Differential pre- and post-synaptic effects of desipramine on cardiac sympathetic nerve terminals in RHF. Am J Physiol Heart Circ Physiol. 2002;283:H1863–H1872[Abstract/Free Full Text]
33. Shite J, Dong E, Kawai H, Stevens SY, Liang C-s. Selegiline improves cardiac noradrenergic nerve terminal function and ß-adrenergic responsiveness in heart failure. Am J Physiol Heart Circ Physiol. 2000;279:H1283–H1290[Abstract/Free Full Text]
34. Takechi S, Nomura A, Shimono H, et al. Recovery of cardiac norepinephrine concentration and tyrosine hydroxylase activity by the central 2-adrenoceptor agonist guanabenz in rats with aortic constriction. J Cardiovasc Pharmacol. 1999;33:409–413[CrossRef][Medline]
35. Brede M, Wiesmann F, Jahns R, et al. Feedback inhibition of catecholamine release by two different 2-adrenoceptor subtypes prevents progression of heart failure. Circulation. 2002;106:2491–2496[Abstract/Free Full Text]
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