Skip to main content
Log in

Sympathetic re-innervation after heart transplantation: dual-isotope neurotransmitter scintigraphy, norepinephrine content and histological examination

  • Original Article
  • Published:
European Journal of Nuclear Medicine Aims and scope Submit manuscript

Abstract

Cardiac transplantation entails surgical disruption of the sympathetic nerve fibres from their somata, resulting in sympathetic denervation. In order to investigate the occurrence of sympathetic re-dnnervation, neurotransmitter scintigraphy using the norepinephrine analogue iodine-123 metaiodobenzylguanidine (MIBG) was performed in 15 patients 2–69 months after transplantation. In addition, norepinephrine content and immunohistochemical reactions of antibodies to Schwarm cell-associated S100 protein, to neuron-specific enolase (NSE) and to norepinephrine were examined in 34 endomyocardial biopsies of 29 patients 1–88 months after transplantation. Anterobasal123I-MIBG uptake indicating partial sympathetic re-dnnervation could be shown in 40% of the scintigraphically investigated patients 37–69 months after transplantation. In immunohistochemical studies 83% of the patients investigated 1–72 months after transplantation showed nerve fibres in their biopsies but not positive reaction to norepinephrine. Significant norepinephrine content indicating re-dnnervation could not be detected in any biopsy. It was concluded that in spite of the lack of norepinephrine content there seemed to be immunohistological and scintigraphic evidence of sympathetic re-dnnervation. An explanation for this contradictory finding may be the reduced or missing norepinephrine storage ability compared to the restored uptake ability of regenerated sympathetic nerve fibres.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Olivari MT, Kubo SH, Braunlin EA, et al. Five-year experience with triple-drug immunosuppressive therapy in cardiac transplantation.Circulation 1990; 82: 276–280.

    Google Scholar 

  2. Stevenson L, Sietsema K, Tillisch J, et al. Exercise capacity of survivors after cardiac transplantation or sustained medical therapy for stable heart failure.Circulation 1990; 81: 78–85.

    PubMed  Google Scholar 

  3. Peiss C, Cooper T, Willman V. Circulatory responses to electrical and reflex activation of the nervous system after cardiac denervation.Circ Res 1966; 19: 153–166.

    Google Scholar 

  4. Klein RL, Lagererantz H, Zimmermann H, eds. Chemical neurotransmission — an introduction. In:Neurotransmitter vesicles. New York: Academic Press; 1982: 16–21.

    Google Scholar 

  5. Kavanagh T, Yacoub M, Mertens D, et al. Cardiorespiratory responses to exercise training after orthotopic cardiac transplantation. Circulation 1988; 77: 162–171.

    PubMed  Google Scholar 

  6. Banner N, Patel N, Cox A, et al. Altered sympathoadrenal response to dynamic exercise in cardiac transplant recipients.Cardiovasc Res 1989; 23: 965–972.

    PubMed  Google Scholar 

  7. Niset G, Piret A, Delbarre N. Functional noninvasive cardiorespiratory evaluation a month and a year after orthotopic heart transplantation. Ann Cardiol Angiol 1988; 37: 9–12.

    Google Scholar 

  8. Beck W, Barnard C, Schrire V. Heart rate after cardiac transplantation.Circulation 1969; 40: 437–445.

    PubMed  Google Scholar 

  9. Dae MW, De Marco T, Botvinick EH, et al. Scintigraphie assessment of MIBG uptake in globally denervated human and canine hearts — implications for clinical studies.J Nucl Med 1992;33:1444–1450.

    PubMed  Google Scholar 

  10. Kaye MP, Tyce GM. Norepinephrine uptake as an indicator of cardiac reinnervation in dogs.Am J Physiol 1978; 253: H289-H294.

    Google Scholar 

  11. Kondo Y, Matheny J, Hardy J. Autonomic reinnervation of cardiac transplants: further observations in dogs and rhesus monkeys.Ann Surg 1972, 176: 24–28.

    Google Scholar 

  12. Schwaiger M, Hutchins GB, Kalff V. Evidence for regional catecholamine uptake and storage sites in the transplanted human heart by positron emission tomography.J Clin Invest 1991;87:1681–1690.

    PubMed  Google Scholar 

  13. 13.Uretzky BF, Murali S, Reddy PS, et al. Development of coronary artery disease in cardiac transplant patients receiving immunosuppressive therapy with cyclosporine and prednisone.Circulation 1987; 76: 827–834.

    PubMed  Google Scholar 

  14. Dae MW, O'Connell W, Botvinick EH, et al. Scintigraphic assessment of regional cardiac adrenergic innervation.Circulation 1989; 79: 634–644.

    PubMed  Google Scholar 

  15. Sisson JC, Wieland DM, Sherman P, et al. Metaiodobenzylguanidine as an index of the adrenergic nervous system integrity and function.J. Nucl Med 1987; 28: 1620–1624.

    PubMed  Google Scholar 

  16. Gürtner C, Hör G, Neuroadrenerge Funktionsszintigraphie des Herzens (Neurotransmitter Mapping): derzeitiger Stand.Nucl Med 1991; 30: 111–114.

    Google Scholar 

  17. Knapp WH, Vyska K, Machula HJ, Notohamiprodijo, Schmidt U, Knust EJ, Gleichmann U. Double-nuclide study of the myocardium using T1-201 and I-123-labeled fatty acids in nonischemic myocardial diseases.Nucl Med 1988; 27:72–78.

    Google Scholar 

  18. Regitz V, Sasse S, Bossaller C, Strasser R, Schüler S, Hetzer R, Fleck E. Myokardialer Katecholamingehalt bei Herzinsuffizienz. Teil 1. Regionale Verteilung in explantierten Herzen. Vergleich zwischen dilatativer Kardiomyopathie und koronarer Herzerkrankung.Z Kardiol 1989; 78: 751–758.

    PubMed  Google Scholar 

  19. Regitz V, Sasse S, Fleck E. Myokardialer Katecholamingehalt bei Herzinsuffizienz. Teil II. Messungen in Endomyokardbiopsien, Referenzsysteme, Normalwerte.Z Kardiol 1989; 78: 759–763.

    PubMed  Google Scholar 

  20. Kantos H, Thames M, Lower R. Responses to electrical and reflex autonomic stimulation in dogs with cardiac transplantation before and after reinnervation.J Thorac Cardiovasc Surg 1970; 59:382–392.

    PubMed  Google Scholar 

  21. Norvell J, Lower R. Degeneration and regeneration of the nerve of the heart after transplantation.Transplantation 1973; 15:337–344.

    PubMed  Google Scholar 

  22. Dae MW De Marco T, Botvinick EH. MIBG uptake at one year post cardiac transplant — evidence for partial reinnervation in man.J Nucl Med 1992; 33: 896.

    Google Scholar 

  23. Regitz V, Bossaller C, Strasser R. Myocardial catecholamine content after heart transplantation.Circulation 1990; 82: 620–623.

    PubMed  Google Scholar 

  24. Bristow M. The surgically denervated transplanted human heart.Circulation 1990; 82: 658–660.

    PubMed  Google Scholar 

  25. Wilson RF, Christensen BV, livari MT. Evidence for structural sympathetic reinnervation after orthotopic cardiac transplantation in humans.Circulation 1991; 83: 1210–1220.

    PubMed  Google Scholar 

  26. Stark RP, McGinn AL, Wilson RE Chest pain in cardiac transplant recipients — evidence of sensory reinnervation after cardiac transplantation.N Engl J Med 1991; 324: 1791–1794.

    PubMed  Google Scholar 

  27. Hartmann A, Maul FD, Huth A, et al. Serial evaluation of left ventricular function by radionuclide ventriculography at rest and during exercise after orthotopic heart transplantation.Eur J Nucl Med 1993; 20: 146–150.

    PubMed  Google Scholar 

  28. Wellman HN, Zipes DP Cardiac sympathetic imaging with radioiodinated metaiodobenzylguanidine (MIBG).Prog Cardiol 1990; 3: 161–174.

    Google Scholar 

  29. Glowniak JV, Turner FE, Gray LL. Iodine-123 metaiodobenzylguanidine imaging of the heart in idiopathic congestive cardiomyopathy and cardiac transplants.J. Nucl Med 1989; 30: 1182–1191.

    PubMed  Google Scholar 

  30. Oyer PE, Stinson EB, Jamieson SW, et al. Cyclosporine in cardiac transplantation: a 2 1/2 follow-up.Transplant Proc. 1983; 15: 2546–2552.

    PubMed  Google Scholar 

  31. Hosenpud JD, Morton MJ, Wilson RA, Pantely GA, Norman DJ, Cobanoglu MA, Starr A. Abdominal exercise hemodynamics in cardiac allograft recipients 1 year after cardiac transplantation.Circulation 1989; 80: 525–532.

    PubMed  Google Scholar 

  32. Vracko R, Throning D, Frederickson RG. Fate of nerve fibres in necrotic, healing and healed rat myocardium.Lab Invest 1990; 4: 490–501.

    Google Scholar 

  33. Jones EG. The nervous tissue. In: Weiss L, ed.Cell and tissue biology. Baltimore: Urban & Schwarzenberg; 1988: 322.

    Google Scholar 

  34. Yamauchi A. Ultrastructure of innervation of the mammalian heart. In: Challice CE, Viragh S, eds.Ultrastructure of the mammalian heart. New York: Academic Press; 1974: 127.

    Google Scholar 

  35. Nakajo M, Shapiro B, Glowniak J. Inverse relationship between cardiac accumulation of meta(131)iodobenzylguanidine and circulating catecholamines in suspected pheochromocytoma.J Nucl Med 1983; 24: 1127–1134.

    PubMed  Google Scholar 

  36. Olivari MT, Levine TB, Ring WS, Simon A, Cohn JN. Normalization of sympathetic nervous function after orthotopic cardiac transplantation in man.Circulation 1987; 76: 62–64.

    Google Scholar 

  37. Glowniak JV, Kilty JE, Amara SG. Evaluation of metaiodobenzylguanidine uptake by norepinephrine, dopamine and serotonin transporters.J Nucl Med 1993; 34: 1140–1146.

    PubMed  Google Scholar 

  38. Kaye MP, Randall WC, Hageman CR. Chronology and mode of reinnervation of the surgically denervated canine heart: functional and chemical correlates.Am J Physiol 1977; 233: H431-H437.

    PubMed  Google Scholar 

  39. Coyle JT, Axelrod J. Development of the uptake and storage of L-(3H)norepinephrine in the rat brain.J Neurochem 1971; 18: 2061–2075.

    PubMed  Google Scholar 

  40. Weinmann P, Foult JM, LeGuludec D, Tamgac F, Rechtmann D, Neumann A, Caillat-Vigneron N, Moretti JL. Dual isotope myocardial imaging: feasibility, advantages and limitations.Eur J Nucl Med 1994; 21: 212–215.

    PubMed  Google Scholar 

  41. Nishimura T, Uchara T, Oka H. Serial assessment of denervated but viable myocardium following acute myocardial infarction by using I-123-MIBG and 201-T1 myocardial SPECT.Jpn J Nucl Med 1990; 27: 709–718.

    Google Scholar 

  42. Herrmann G, Schumm-Draeger P-M, Müller C, Atai E, Wenzel B, Fabian T, Usadel KH, Hübner K. T-lymphocytes, CD68-positive cells and vascularisation in thyroid carcinomas.J Cancer Res Clin Oncol 1994; 120: 651–656.

    PubMed  Google Scholar 

  43. Denniss AR, Marsh JD, Quigg RJ, Gordon JB, Colucci WS. Beta-adrenergic receptor number and adenylate cyclase function in denervated transplanted and cardiomyopathic human hearts.Circulation 1989; 79: 1028–1034.

    PubMed  Google Scholar 

  44. Kahn JK, McGhie I, Akers MS, Sills MN, Faber TL, Kulkarni PV, Willerson JT, Corbett JR. Quantitative rotational tomography with T1-201 and Tc-99m-sestamibi: a direct comparison in normal individuals and patients with coronary artery disease.Circulation 1989; 79: 1282–1293.

    PubMed  Google Scholar 

  45. Iskandrian AS, Heo J, Kong B, Lyons E, Marsch S. Use of Tc99m sestamibi in assessing left ventricular perfusion and function at rest and during exercise in coronary artery disease, and comparison with coronary arteriography and exercise T1-201 SPECT imaging.Am Coll Cardiol 1989; 64: 270–275.

    Google Scholar 

  46. Johnson LL, Seldin DW, Keller AM, Wall RM, Bhatia K, Bingham CO, Tresgallo ME. Dual isotope thallium and indium antimyosin SPECT imaging to identify acute infarct patients at further ischemic risk.Circulation 1990; 81: 37–45.

    PubMed  Google Scholar 

  47. Devous MD, Lowe JL, Payne JK. Dual-isotope brain SPECT imaging with technetium and iodine-123: validation by phantom studies.J Nucl Med 1992; 33: 2030–2035.

    PubMed  Google Scholar 

  48. Lowe VJ, Greer KL, Hanson MW, Jaszczak RJ, Coleman RE. Cardiac phantom evaluation of simultaneously acquired dualisotope rest thallium-201/stress technetium-99m SPECT images.J Nucl Med 1993; 34: 1998–2006.

    PubMed  Google Scholar 

  49. Yang DC, Ragasa E, Gould L, Huang M, Reddy CVR, Saul B, Schifter D, Rainaldi D, Feld C, Tank RA, Lee SY, Giovanniello J. Radionuclide simultaneous dual-isotope stress myocardial perfusion study using the three window technique.Clin Nucl Med 1993; 18: 852–857.

    PubMed  Google Scholar 

  50. Crawley JCW, Smith T, Jain D, Raval U, Zanelli GD, Lahiri A. Problems and pitfalls in dual isotope imaging. In: Hoefer R, Bergmann H, eds.Radioactive isotopes in clinical medicine and research. 18th International Symposium, Badgastein, 11–14 January 1988. Stuttgart: Schattauer; 1988: 567–571.

    Google Scholar 

  51. Nakajima K, Taki J, Bonko H, Shimuzu M, Muramori A, Tonami N, Hisada K. Error of uptake in dual energy acquisition with T1-201 and I-123-labeled radiopharmaceuticals.Eur J Nucl Med 1990; 16: 595–599.

    PubMed  Google Scholar 

  52. Crawley J, Smith T. Dual energy imaging.Eur J Nucl Med 1991; 18: 70.

    PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and permissions

About this article

Cite this article

Guertner, C., Krause, B.J., Klepzig, H. et al. Sympathetic re-innervation after heart transplantation: dual-isotope neurotransmitter scintigraphy, norepinephrine content and histological examination. Eur J Nucl Med 22, 443–452 (1995). https://doi.org/10.1007/BF00839059

Download citation

  • Received:

  • Revised:

  • Issue Date:

  • DOI: https://doi.org/10.1007/BF00839059

Key words

Navigation