Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Diagnostic and prognostic imaging of the cardiac sympathetic nervous system

Nature Clinical Practice Cardiovascular Medicine volume 5, pages S79–S86 (2008)Cite this article

Abstract

Individuals with systolic dysfunction congestive heart failure may have decreased neuronal density, decreased neuronal function (reuptake or retention of norepinephrine), or a combination of these, plus reduction in postsynaptic β-receptor density. Cardiac neuronal distribution and function can be imaged with standard γ cameras and PET using radiolabeled analogs of norepinephrine. Postsynaptic β-adrenergic receptor distribution and density can be determined using PET. Multiple imaging studies of the presynaptic component have reported that those individuals with the lowest retention or fastest washout of the radiolabeled analogs have a much greater annual mortality than do those with greater retention or slower washout rate. The results of some studies have suggested that the image abnormalities are better predictors of death than are more common predictors of outcome such as ejection fraction, heart rate variability, and microvolt T-wave alternans. The variability between these studies makes it unclear which measure of presynaptic dysfunction is the most predictive. β-Receptor imaging has not been evaluated as extensively as a prognostic tool as has presynaptic imaging. Preliminary data suggest that regional mismatch between β-receptors and presynaptic norepinephrine transporter function may serve as a marker for adverse outcome.

Key Points

  • Utilizing radiolabeled norepinephrine analogues, standard γ camera and PET have been used to image norepinephrine uptake/storage by the presynaptic cardiac sympathetic nervous system

  • β-Adrenergic receptors can only be imaged with PET

  • For many etiologies of systolic congestive heart failure, there is decreased uptake or incomplete retention of norepinephrine by the presynaptic nervous system, which can be identified by evaluating changes in radiotracer activity over time

  • Heart failure patients with the poorest retention or more rapid washout of norepinephrine analogue by either imaging modality have a worse survival rate than those with a higher or normal retention/washout

  • β-Adrenergic receptor density is not necessarily abnormal in regions of abnormal presynaptic function and heart failure patients, as a group, have much greater regional mismatch between β-receptor density and presynaptic function than do normal subjects

  • Preliminary data suggest that heart failure patients with the greatest heterogeneity of mismatch between postsynaptic and presynaptic function have worse outcomes than those with less heterogeneity

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Planar scintigraphy images of early (30 min) and late (240 min) heart MIBG uptake and corresponding SPECT images of late uptake and myocardial perfusion.
Figure 2: Short-axis PET images of mHED and carbon-11-labeled CGP 12177 left ventricular activity in a patient with NYHA class III congestive heart failure due to ischemic cardiomyopathy.
Figure 3: Box and whisker plot of the heterogeneity of the ratio between β-adrenergic receptor density and norepinephrine transport function in 13 patients with ischemic heart failure.

Similar content being viewed by others

References

  1. Wieland DM et al. (1981) Myocardial imaging with a radioiodinated norepinephrine storage analog. J Nucl Med 22: 22–31

    CAS  PubMed  Google Scholar 

  2. DeGrado TR et al. (2000) Tracer kinetic modeling in nuclear cardiology. J Nucl Cardiol 7: 686–700

    Article  CAS  Google Scholar 

  3. Schwaiger M et al. (1990) Noninvasive evaluation of sympathetic nervous system in human heart by positron emission tomography. Circulation 82: 457–464

    Article  CAS  Google Scholar 

  4. Delforge J et al. (1991) Cardiac beta-adrenergic receptor density measured in vivo using PET, CGP 12177, and a new graphical method. J Nucl Med 32: 739–748

    CAS  PubMed  Google Scholar 

  5. Doze P et al. (2002) Quantification of beta-adrenoceptor density in the human heart with (S)-[11C]CGP 12388 and a tracer kinetic model. Eur J Nucl Med Mol Imaging 29: 295–304

    Article  CAS  Google Scholar 

  6. Syrota A et al. (1984) Kinetics of in vivo binding of antagonist to muscarinic cholinergic receptor in the human heart studied by positron emission tomography. Life Sci 35: 937–945

    Article  CAS  Google Scholar 

  7. Packer M (1992) The neurohormonal hypothesis: a theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol 26: 248–254

    Article  Google Scholar 

  8. Francis GS et al. (1990) Comparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure: a substudy of the Studies of Left Ventricular Dysfunction (SOLVD). Circulation 82: 1724–1729

    Article  CAS  Google Scholar 

  9. Böhm M et al. (1995) Evidence for reduction of norepinephrine uptake sites in the failing human heart. J Am Coll Cardiol 25: 146–153

    Article  Google Scholar 

  10. Hasking G et al. (1986) Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation 73: 615–621

    Article  CAS  Google Scholar 

  11. Eisenhofer G et al. (1996) Cardiac sympathetic nerve function in congestive heart failure. Circulation 93: 1667–1676

    Article  CAS  Google Scholar 

  12. Merlet P et al. (1999) prognostic value of MIBG imaging in idiopathic dilated cardiomyopathy. J Nucl Med 40: 917–923

    CAS  PubMed  Google Scholar 

  13. Parthenakis FI et al. (2002) Segmental pattern of myocardial sympathetic denervation in idiopathic dilated cardiomyopathy: relationship to regional wall motion and myocardial perfusion abnormalities. J Nucl Cardiol 9: 15–22

    Article  CAS  Google Scholar 

  14. Cohen-Solal A et al. (1999) Cardiac metaiodobenzylguanidine uptake in patients with moderate chronic heart failure: relationship with peak oxygen uptake and prognosis. J Am Coll Cardiol 33: 759–766

    Article  CAS  Google Scholar 

  15. Hartmann F et al. (1999) Regional patterns of myocardial sympathetic denervation in dilated cardiomyopathy: an analysis using carbon-11 hydroxyephedrine and positron emission tomography. Heart 81: 262–270

    Article  CAS  Google Scholar 

  16. Vesalainen RK et al. (1999) Cardiac positron emission tomography imaging with [11C] hydroxyephedrine, a specific tracer for sympathetic nerve endings, and its functional correlates in congestive heart failure. Am J Cardiol 84: 568–574

    Article  CAS  Google Scholar 

  17. Link JM et al. (2003) PET measures of pre- and post-synaptic cardiac beta adrenergic function. Nucl Med Biol 30: 795–803

    Article  CAS  Google Scholar 

  18. Merlet P et al. (1992) Prognostic value of cardiac metaiodobenzylguanidine imaging in patients with heart failure. J Nucl Med 33: 471–477

    CAS  PubMed  Google Scholar 

  19. Kyuma M et al. (2004) Incremental prognostic implications of brain natriuretic peptide, cardiac sympathetic nerve innervation, and noncardiac disorders in patients with heart failure. J Nucl Med 45: 155–163

    CAS  PubMed  Google Scholar 

  20. Nakata T et al. (2003) Prognostic implications of an initial loss of cardiac metaiodobenzylguanidine uptake and diabetes mellitus in patients with left ventricular dysfunction. J Card Fail 9: 113–121

    Article  CAS  Google Scholar 

  21. Chen J et al. (2006) Improved quantification in 123I cardiac SPECT imaging with deconvolution of septal penetration. Nucl Med Commun 27: 551–558

    Article  Google Scholar 

  22. Gerson MC et al. (2003) Sympathetic nervous system function as measured by I-123 metaiodobenzylguanidine predicts transplant-free survival in heart failure patients with idiopathic dilated cardiomyopathy. J Card Fail 9: 384–391

    Article  Google Scholar 

  23. Yamada T et al. (2003) Comparison of the prognostic value of cardiac iodine-123 metaiodobenzylguanidine imaging and heart rate variability in patients with chronic heart failure: a prospective study. J Am Coll Cardiol 41: 231–238

    Article  Google Scholar 

  24. Arimoto T et al. (2007) Cardiac sympathetic denervation and ongoing myocardial damage for prognosis in early stages of heart failure. J Card Fail 13: 34–41

    Article  Google Scholar 

  25. Nakata T et al. (1998) Cardiac death prediction and impaired cardiac sympathetic innervation assessed by MIBG in patients with failing and nonfailing hearts. J Nucl Cardiol 5: 579–590

    Article  CAS  Google Scholar 

  26. Wakabayashi T et al. (2001) Assessment of underlying etiology and cardiac sympathetic innervation to identify patients at high risk of cardiac death. J Nucl Med 42: 1757–1767

    CAS  PubMed  Google Scholar 

  27. Nakata T et al. (1998) Cardiac death prediction and impaired cardiac sympathetic innervation assessed by MIBG in patients with failing and nonfailing hearts. J Nucl Cardiol 5: 579–590

    Article  CAS  Google Scholar 

  28. Kioka H et al. (2007) Prediction of sudden death by using cardiac iodine-123 metaiodobenzylguanidine imaging in patients with mild to moderate chronic heart failure. Heart 93: 1213–1218

    Article  Google Scholar 

  29. Mozaffarian D et al. (2007) Prediction of mode of death in heart failure: the Seattle Heart Failure Model. Circulation 116: 392–398

    Article  Google Scholar 

  30. Pietila M et al. (2001) Reduced myocardial carbon-11 hydroxyephedrine retention is associated with poor prognosis in chronic heart failure. Eur J Nucl Med 28: 373–376

    Article  CAS  Google Scholar 

  31. Fallavollita JA et al. (2006) Prediction of arrhythmic events with positron emission tomography: PAREPET study design and methods. Contemp Clin Trials 27: 374–388

    Article  Google Scholar 

  32. Bristow MR et al. (1986) Beta 1- and beta 2-adrenergic receptor subpopulations in nonfailing and failing human ventricular myocardium: coupling of both receptor subtypes to muscle contraction and selective b1-adrenoceptor down-regulation in heart failure. Circ Res 59: 297–309

    Article  CAS  Google Scholar 

  33. Merlet P et al. (1993) Positron emission tomography with 11C CGP-12177 to assess beta-adrenergic receptor concentration in idiopathic dilated cardiomyopathy. Circulation 87: 1169–1178

    Article  CAS  Google Scholar 

  34. Ungerer M et al. (1998) Regional in vivo and in vitro characterization of autonomic innervation in cardiomyopathic human heart. Circulation 97: 174–180

    Article  CAS  Google Scholar 

  35. Janka HU (1996) Increased cardiovascular morbidity and mortality in diabetes mellitus: identification of the high risk patient. Diabetes Res Clin Pract 30 (Suppl): S85–S88

    Article  Google Scholar 

  36. Jouven X et al. (1999) Predicting sudden death in the population: the Paris Prospective Study I. Circulation 99: 1978–1983

    Article  CAS  Google Scholar 

  37. Kim SJ et al. (1996) Evaluation of cardiac sympathetic neuronal integrity in diabetic patients using iodine-123 metaiodobenzylguanidine. Eur J Nucl Med 23: 401–406

    Article  CAS  Google Scholar 

  38. Muhr-Becker D et al. (1999) Scintigraphically assessed cardiac sympathetic dysinnervation in poorly controlled type 1 diabetes mellitus: one-year follow-up with improved metabolic control. Exp Clin Endocrinol Diabetes 107: 306–312

    Article  CAS  Google Scholar 

  39. Stevens MJ et al. (1999) Regression and progression of cardiac sympathetic dysinnervation complicating diabetes: an assessment by C-11 hydroxyephedrine and positron emission tomography. Metabolism 48: 92–101

    Article  CAS  Google Scholar 

  40. Schnell O et al. (2002) Cardiac sympathetic dysinnervation in Type 2 diabetes mellitus with and without ECG-based cardiac autonomic neuropathy. J Diabetes Complications 16: 220–227

    Article  Google Scholar 

  41. Pop-Busui R et al. (2004) Sympathetic dysfunction in type 1 diabetes: association with impaired myocardial blood flow reserve and diastolic dysfunction. J Am Coll Cardiol 44: 2368–2374

    Article  CAS  Google Scholar 

  42. Nagamachi S et al. (2006) Prognostic value of cardiac I-123 metaiodobenzylguanidine imaging in patients with non-insulin-dependent diabetes mellitus. J Nucl Cardiol 13: 34–42

    Article  Google Scholar 

  43. Schäfers M et al. (1998) Cardiac sympathetic innervation in patients with idiopathic right ventricular outflow tract tachycardia. J Am Coll Cardiol 32: 181–186

    Article  Google Scholar 

  44. Wichter T et al. (2000) Abnormalities of cardiac sympathetic innervation in arrhythmogenic right ventricular cardiomyopathy: quantitative assessment of presynaptic norepinephrine reuptake and postsynaptic beta-adrenergic receptor density with positron emission tomography. Circulation 101: 1552–1558

    Article  CAS  Google Scholar 

  45. Kies P et al. (2004) Abnormal myocardial presynaptic norepinephrine recycling in patients with Brugada syndrome. Circulation 110: 3017–3022

    Article  CAS  Google Scholar 

  46. Wichter T et al. (2002) Cardiac autonomic dysfunction in Brugada syndrome. Circulation 105: 702–706

    Article  Google Scholar 

  47. Paul M et al. (2006) Impact of sympathetic innervation on recurrent life-threatening arrhythmias in the follow-up of patients with idiopathic ventricular fibrillation. Eur J Nucl Med Mol Imaging 33: 866–870

    Article  Google Scholar 

  48. Bengel FM and Schwaiger M (2004) Assessment of cardiac sympathetic neuronal function using PET imaging. J Nucl Cardiol 11: 603–616

    Article  Google Scholar 

  49. Wamashina S and Yamazaki J (2007) Neuronal imaging using SPECT. Eur J Nucl Med Mol Imaging 34 (Suppl 1): S62–S73

    Article  Google Scholar 

  50. Chen GP et al. (2005) Cardiac receptor physiology and imaging: an update. J Nucl Cardiol 12: 714–730

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. JM Link is an Associate Professor of Radiology (Nuclear Medicine) and is Director of the PET Radiochemistry Laboratories at the University of Washington, and JH Caldwell is Professor of Medicine (Cardiology) and Radiology and Adjunct Professor of Bioengineering at the University of Washington School of Medicine and Director of Nuclear Cardiology for the University of Washington Hospitals, Seattle, WA, USA.,

    Jeanne M Link & James H Caldwell

Authors
  1. James H Caldwell
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James H Caldwell.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Link, J., Caldwell, J. Diagnostic and prognostic imaging of the cardiac sympathetic nervous system. Nat Rev Cardiol 5 (Suppl 2), S79–S86 (2008). https://doi.org/10.1038/ncpcardio1150

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncpcardio1150

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing