Skip to main content
SpringerLink
Log in

Cardiac sympathetic hypo-innervation in familial dysautonomia

  • RESEARCH ARTICLE
  • Published:
Clinical Autonomic Research Aims and scope Submit manuscript

Abstract

Objective

Familial dysautonomia (FD) involves incomplete development of the sympathetic nervous system. Whether such loss extends to sympathetic innervation of the heart has been unknown. This study used 6-[18F]fluorodopamine neuroimaging to assess cardiac sympathetic innervation and function in FD.

Methods

Six adult FD patients underwent thoracic PET scanning for 30 minutes after i.v. 6-[18F]fluorodopamine injection, as did healthy volunteers without (N = 21) or with (N = 10) pre-treatment by desipramine, which interferes with neuronal uptake and thereby simulates effects of noradrenergic denervation. Effective rate constants for uptake and loss were calculated using a single compartment pharmacokinetic model.

Results

FD patients had decreased uptake and accelerated loss of 6-[18F]fluorodopamine-derived radioactivity in the interventricular myocardial septum (P = 0.009, P = 0.05) and ventricular free wall (P = 0.007, P < 0.001), compared to untreated controls. Desipramine-treated subjects had decreased uptake but normal loss of 6-[18F]fluorodopamine-derived radioactivity.

Conclusions

FD involves cardiac noradrenergic hypo-innervation. Since accelerated loss of 6-[18F]fluorodopamine-derived radioactivity cannot be explained by decreased neuronal uptake alone, FD may also involve augmented NE loss from extant terminals.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Axelrod FB (2006) A world without pain or tears. Clin Auton Res 16:90–96

    Article  PubMed  Google Scholar 

  2. Axelrod FB, Goldberg JD, Ye XY, Maayan C (2002) Survival in familial dysautonomia: impact of early intervention. J Pediatr 141:518–523

    Article  PubMed  Google Scholar 

  3. Close P, Hawkes N, Cornez I, Creppe C, Lambert CA, Rogister B, Siebenlist U, Merville MP, Slaugenhaupt SA, Bours V, Svejstrup JQ, Chariot A (2006) Transcription impairment and cell migration defects in elongator-depleted cells: implication for familial dysautonomia. Mol Cell 22:521–531

    Article  PubMed  CAS  Google Scholar 

  4. Freedman LS, Ebstein RP, Goldstein M, Axelrod FB, Dancis J (1975) Serum dopamine-beta-hydroxylase in familial dysautonomia. J Lab Clin Med 85:1008–1012

    PubMed  CAS  Google Scholar 

  5. Glickstein JS, Axelrod FB, Friedman D (1999) Electrocardiographic repolarization abnormalities in familial dysautonomia: an indicator of cardiac autonomic dysfunction. Clin Auton Res 9:109–112

    Article  PubMed  CAS  Google Scholar 

  6. Gold-von Simson G, Rutkowski M, Berlin D, Axelrod FB (2005) Pacemakers in patients with familial dysautonomia–a review of experience with 20 patients. Clin Auton Res 15:15–20

    Article  PubMed  Google Scholar 

  7. Goldstein DS, Eisenhofer G, Dunn BB, Armando I, Lenders J, Grossman E, Holmes C, Kirk KL, Bacharach S, Adams R, Herscovitch P, Kopin IJ (1993) Positron emission tomographic imaging of cardiac sympathetic innervation using 6-[18F]fluorodopamine: initial findings in humans. J Am Coll Cardiol 22:1961–1971

    Article  PubMed  CAS  Google Scholar 

  8. Goldstein DS, Grossman E, Tamrat M, Chang PC, Eisenhofer G, Bacher J, Kirk KL, Bacharach S, Kopin IJ (1991) Positron emission imaging of cardiac sympathetic innervation and function using 18F-6-fluorodopamine: effects of chemical sympathectomy by 6-hydroxydopamine. J Hypertens 9:417–423

    Article  PubMed  CAS  Google Scholar 

  9. Goldstein DS, Holmes C, Li ST, Bruce S, Metman LV, Cannon RO 3rd (2000) Cardiac sympathetic denervation in Parkinson disease. Ann Intern Med 133:338–347

    PubMed  CAS  Google Scholar 

  10. Goldstein DS, Holmes C, Stuhlmuller JE, Lenders JWM, Kopin IJ (1997) 6-[18F]Fluorodopamine positron emission tomographic scanning in the assessment of cardiac sympathoneural function–studies in normal humans. Clin Auton Res 7:17–29

    Article  PubMed  CAS  Google Scholar 

  11. Goldstein DS, Katzper M, Linares OA, Kopin IJ (2002) Kinetic model for the fate of the sympathoneural imaging agent 6-[18F]fluorodopamine in the human heart: a novel means to assess cardiac sympathetic neuronal function. Naunyn-Schmiedeberg’s Arch Pharmacol 365:38–49

    Article  CAS  Google Scholar 

  12. Goodall MC, Gitlow SE, Alton H (1971) Decreased noradrenaline (norepinephrine) synthesis in familial dysautonomia. J Clin Invest 50:2734–2740

    Article  PubMed  CAS  Google Scholar 

  13. Kashihara K, Ohno M, Kawada S, Okumura Y (2006) Reduced cardiac uptake and enhanced washout of 123I-MIBG in pure autonomic failure occurs conjointly with Parkinson’s disease and dementia with Lewy bodies. J Nucl Med 47:1099–1101

    PubMed  CAS  Google Scholar 

  14. Pearson J, Brandeis L, Goldstein M (1979) Tyrosine hydroxylase immunoreactivity in familial dysautonomia. Science 206:71–72

    Article  PubMed  CAS  Google Scholar 

  15. Pearson J, Dancis J, Axelrod F, Grover N (1975) The sural nerve in familial dysautonomia. J Neuropathol Exp Neurol 34:413–424

    Article  PubMed  CAS  Google Scholar 

  16. Pearson J, Gallo G, Gluck M, Axelrod F (1980) Renal disease in familial dysautonomia. Kidney Int 17:102–112

    Article  PubMed  CAS  Google Scholar 

  17. Pearson J, Pytel BA (1978) Quantitative studies of sympathetic ganglia and spinal cord intermedio-lateral gray columns in familial dysautonomia. J Neurol Sci 39:47–59

    Article  PubMed  CAS  Google Scholar 

  18. Rotstein A, Charrow J, Deal BJ (2007) Documented transient third-degree atrioventricular block and asystole in a child with familial dysautonomia. Pediatr Cardiol

  19. Slaugenhaupt SA, Blumenfeld A, Gill SP, Leyne M, Mull J, Cuajungco MP, Liebert CB, Chadwick B, Idelson M, Reznik L, Robbins C, Makalowska I, Brownstein M, Krappmann D, Scheidereit C, Maayan C, Axelrod FB, Gusella JF (2001) Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet 68:598–605

    Article  PubMed  CAS  Google Scholar 

  20. Slaugenhaupt SA, Mull J, Leyne M, Cuajungco MP, Gill SP, Hims MM, Quintero F, Axelrod FB, Gusella JF (2004) Rescue of a human mRNA splicing defect by the plant cytokinin kinetin. Hum Mol Genet 13:429–436

    Article  PubMed  CAS  Google Scholar 

  21. Smith AA, Taylor T, Wortis B (1963) Abnormal catechol amine metabolism in familial dysautonomia. N Engl J Med 268:705–707

    PubMed  CAS  Google Scholar 

  22. Taki J, Nakajima K, Hwang EH, Matsunari I, Komai K, Yoshita M, Sakajiri K, Tonami N (2000) Peripheral sympathetic dysfunction in patients with Parkinson’s disease without autonomic failure is heart selective and disease specific. Eur J Nucl Med 27:566–573

    Article  PubMed  CAS  Google Scholar 

  23. Weinshilboum RM, Axelrod J (1971) Reduced plasma dopamine-beta-hydroxylase activity in familial dysautonomia. N Engl J Med 285:938–942

    PubMed  CAS  Google Scholar 

  24. Ziegler MG, Lake CR, Kopin IJ (1976) Deficient sympathetic nervous response in familial dysautonomia. N Engl J Med 294:630–633

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This research was supported by the Intramural Research Program of the NIH, National Institute of Neurological Disorders and Stroke.

Author information

Authors and Affiliations

  1. Clinical Neurocardiology Section, National Institute of Neurological Disorders and Stroke, NIH, 10 Center Drive MSC-1620, Building 10 Room 6N252, Bethesda, MD, 20892-1620, USA

    David S. Goldstein MD, PhD, Basil Eldadah MD, PhD & Yehonatan Sharabi MD

  2. New York University School of Medicine, New York, NY, USA

    Felicia B. Axelrod MD

Authors
  1. David S. Goldstein MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Basil Eldadah MD, PhD
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yehonatan Sharabi MD
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Felicia B. Axelrod MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to David S. Goldstein MD, PhD.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Goldstein, D.S., Eldadah, B., Sharabi, Y. et al. Cardiac sympathetic hypo-innervation in familial dysautonomia. Clin Auton Res 18, 115–119 (2008). https://doi.org/10.1007/s10286-008-0464-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10286-008-0464-1

Keywords

Search

Navigation