Skip to main content
PMC home page
Heart logoLink to Heart
. 1999 Mar;81(3):262–270. doi: 10.1136/hrt.81.3.262

Regional patterns of myocardial sympathetic denervation in dilated cardiomyopathy: an analysis using carbon-11 hydroxyephedrine and positron emission tomography

F Hartmann 1, S Ziegler 1, S Nekolla 1, M Hadamitzky 1, M Seyfarth 1, G Richardt 1, M Schwaiger 1
PMCID: PMC1728957  PMID: 10026349

Abstract

OBJECTIVE—To assess presynaptic function of cardiac autonomic innervation in patients with advanced congestive heart failure using positron emission tomography (PET) and the recently developed radiolabelled catecholamine analogue carbon-11 hydroxyephedrine (HED) as a marker for neuronal catecholamine uptake function. 
DESIGN AND PATIENTS—29 patients suffering from dilated cardiomyopathy with moderate to severe heart failure were compared with eight healthy controls. Perfusion scan was followed by HED dynamic PET imaging of cardiac sympathetic innervation. The scintigraphic results were compared with markers of disease severity and the degree of sympathetic dysfunction assessed by means of heart rate variability.
RESULTS—In contrast to nearly normal perfusions, mean (SD) HED retention in dilated cardiomyopathy patients was abnormal in 64 (32)% of the left ventricle. Absolute myocardial HED retention was 10.7 (1.0)%/min in controls v 6.2 (1.6)%/min in dilated cardiomyopathy patients (p < 0.001). Moreover, significant regional reduction of HED retention was demonstrated in apical and inferoapical segments. HED retention was significantly correlated with New York Heart Association functional class (r = −0.55, p = 0.002) and ejection fraction (r = 0.63, p < 0.001), but not, however, with plasma noradrenaline concentrations as well as parameters of heart rate variability. 
CONCLUSIONS—In this study, using PET in combination with HED in patients with dilated cardiomyopathy, not only global reduction but also regional abnormalities of cardiac sympathetic tracer uptake were demonstrated. The degree of abnormality was positively correlated to markers of severity of heart failure. The pathogenetic mechanisms leading to the regional differences of neuronal damage as well as the prognostic significance of these findings remain to be defined.

 Keywords: heart failure; dilated cardiomyopathy; C-11 hydroxyephedrine; positron emission tomography; sympathetic nervous system

Full Text

The Full Text of this article is available as a PDF (199.6 KB).

Figure 1  .

Figure 1  

Open in a new tab

Chemical structures of noradrenaline and C-11 hydroxyephedrine (HED).

Figure 2  .

Figure 2  

Open in a new tab

Imaging protocol. After positioning in the tomograph, a bolus injection of 185-370 MBq (5-10 mCi) of N-13 ammonia was followed by a 20 minute static acquisition, commencing three minutes after injection. Then a 10 minute transmission study was acquired. After waiting one hour for N-13 decay, neuronal imaging of the heart was performed after bolus injection of 740 MBq (20 mCi) of C-11 hydroxyephedrine, with a subsequent 40 minute dynamic data acquisition in frame mode (14 frames) to determine tracer activity in both blood and myocardium.

Figure 3  .

Figure 3  

Open in a new tab

Scheme of the polar map areas and the corresponding left ventricular regions.1, apical; 2, anterior apical; 3, lateral apical; 4, inferior apical; 5, septal apical; 6, anterior basal; 7, lateral basal; 8, inferior basal; 9, septal basal.

Figure 4  .

Figure 4  

Open in a new tab

PET study of a 50 year old patient with moderate heart failure and a left ventricular ejection fraction of 30%. Blood flow images showed a normal perfusion pattern, but HED retention index was reduced by 20% compared to normal values. The regional tracer distribution appeared normal on visual inspection with only a small region of abnormal tracer retention in the distal inferior left ventricle.

Figure 5  .

Figure 5  

Open in a new tab

PET study of a 43 year old patient with severe heart failure and an ejection fraction of 16%. Blood flow images again were normal, but HED images showed a regional reduction of tracer retention in the distal lateral and inferior wall.

Figure 6  .

Figure 6  

Open in a new tab

Extent of neuronal and blood flow inhomogeneities in dilated cardiomyopathy, expressed as percentage of polar map area < 2.5 SD below control values (% left ventricular). HED retention was significantly different in NYHA II v NYHA III patients (p < 0.01).

Figure 7  .

Figure 7  

Open in a new tab

Absolute tissue retention index of C-11 HED at 40 minutes, normalised to the integral arterial input function, was significantly reduced in dilated cardiomyopathy patients. The degree of reduction corresponded to NYHA functional class.

Figure 8  .

Figure 8  

Open in a new tab

Maps of flow (left side) and C-11 HED retention (right side) in dilated cardiomyopathy patients. Regional tracer activity is expressed as a percentage of the individual maximum of each polar map. Despite a homogenous perfusion pattern, HED retention is reduced significantly (compared to the corresponding perfusion values) in the apical segments.

Figure 9  .

Figure 9  

Open in a new tab

Regional C-11 HED retention index (left side) was progressively reduced from proximal to distal (p < 0.05 in the inferoapical and p < 0.001 in the apical segment). Regional HED/flow ratio (right side) in dilated cardiomyopathy patients. Values close to unity mean correspondence between flow and HED retention and were found in the basal segments. However, they were progressively reduced from basal to apical myocardium (p < 0.05 in the apical and inferoapical segment).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Allman K. C., Stevens M. J., Wieland D. M., Hutchins G. D., Wolfe E. R., Jr, Greene D. A., Schwaiger M. Noninvasive assessment of cardiac diabetic neuropathy by carbon-11 hydroxyephedrine and positron emission tomography. J Am Coll Cardiol. 1993 Nov 1;22(5):1425–1432. doi: 10.1016/0735-1097(93)90553-d. [DOI] [PubMed] [Google Scholar]
  2. Allman K. C., Wieland D. M., Muzik O., Degrado T. R., Wolfe E. R., Jr, Schwaiger M. Carbon-11 hydroxyephedrine with positron emission tomography for serial assessment of cardiac adrenergic neuronal function after acute myocardial infarction in humans. J Am Coll Cardiol. 1993 Aug;22(2):368–375. doi: 10.1016/0735-1097(93)90039-4. [DOI] [PubMed] [Google Scholar]
  3. Bristow M. R., Feldman A. M. Changes in the receptor-G protein-adenylyl cyclase system in heart failure from various types of heart muscle disease. Basic Res Cardiol. 1992;87 (Suppl 1):15–35. doi: 10.1007/978-3-642-72474-9_2. [DOI] [PubMed] [Google Scholar]
  4. Bristow M. R., Ginsburg R., Umans V., Fowler M., Minobe W., Rasmussen R., Zera P., Menlove R., Shah P., Jamieson S. 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 beta 1-receptor down-regulation in heart failure. Circ Res. 1986 Sep;59(3):297–309. doi: 10.1161/01.res.59.3.297. [DOI] [PubMed] [Google Scholar]
  5. Brodde O. E. Beta 1- and beta 2-adrenoceptors in the human heart: properties, function, and alterations in chronic heart failure. Pharmacol Rev. 1991 Jun;43(2):203–242. [PubMed] [Google Scholar]
  6. Böhm M., Gierschik P., Jakobs K. H., Pieske B., Schnabel P., Ungerer M., Erdmann E. Increase of Gi alpha in human hearts with dilated but not ischemic cardiomyopathy. Circulation. 1990 Oct;82(4):1249–1265. doi: 10.1161/01.cir.82.4.1249. [DOI] [PubMed] [Google Scholar]
  7. Böhm M., La Rosée K., Schwinger R. H., Erdmann E. Evidence for reduction of norepinephrine uptake sites in the failing human heart. J Am Coll Cardiol. 1995 Jan;25(1):146–153. doi: 10.1016/0735-1097(94)00353-r. [DOI] [PubMed] [Google Scholar]
  8. Calkins H., Allman K., Bolling S., Kirsch M., Wieland D., Morady F., Schwaiger M. Correlation between scintigraphic evidence of regional sympathetic neuronal dysfunction and ventricular refractoriness in the human heart. Circulation. 1993 Jul;88(1):172–179. doi: 10.1161/01.cir.88.1.172. [DOI] [PubMed] [Google Scholar]
  9. Cohn J. N., Levine T. B., Olivari M. T., Garberg V., Lura D., Francis G. S., Simon A. B., Rector T. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984 Sep 27;311(13):819–823. doi: 10.1056/NEJM198409273111303. [DOI] [PubMed] [Google Scholar]
  10. DeGrado T. R., Hutchins G. D., Toorongian S. A., Wieland D. M., Schwaiger M. Myocardial kinetics of carbon-11-meta-hydroxyephedrine: retention mechanisms and effects of norepinephrine. J Nucl Med. 1993 Aug;34(8):1287–1293. [PubMed] [Google Scholar]
  11. Fowler M. B., Laser J. A., Hopkins G. L., Minobe W., Bristow M. R. Assessment of the beta-adrenergic receptor pathway in the intact failing human heart: progressive receptor down-regulation and subsensitivity to agonist response. Circulation. 1986 Dec;74(6):1290–1302. doi: 10.1161/01.cir.74.6.1290. [DOI] [PubMed] [Google Scholar]
  12. Francis G. S., Benedict C., Johnstone D. E., Kirlin P. C., Nicklas J., Liang C. S., Kubo S. H., Rudin-Toretsky E., Yusuf S. 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. 1990 Nov;82(5):1724–1729. doi: 10.1161/01.cir.82.5.1724. [DOI] [PubMed] [Google Scholar]
  13. Francis G. S., Goldsmith S. R., Levine T. B., Olivari M. T., Cohn J. N. The neurohumoral axis in congestive heart failure. Ann Intern Med. 1984 Sep;101(3):370–377. doi: 10.7326/0003-4819-101-3-370. [DOI] [PubMed] [Google Scholar]
  14. Francis G. S., Rector T. S., Cohn J. N. Sequential neurohumoral measurements in patients with congestive heart failure. Am Heart J. 1988 Dec;116(6 Pt 1):1464–1468. doi: 10.1016/0002-8703(88)90729-6. [DOI] [PubMed] [Google Scholar]
  15. Glowniak J. V. Cardiac studies with metaiodobenzylguanidine: a critique of methods and interpretation of results. J Nucl Med. 1995 Nov;36(11):2133–2137. [PubMed] [Google Scholar]
  16. Glowniak J. V., Turner F. E., Gray L. L., Palac R. T., Lagunas-Solar M. C., Woodward W. R. Iodine-123 metaiodobenzylguanidine imaging of the heart in idiopathic congestive cardiomyopathy and cardiac transplants. J Nucl Med. 1989 Jul;30(7):1182–1191. [PubMed] [Google Scholar]
  17. Glowniak J. V., Turner F. E., Gray L. L., Palac R. T., Lagunas-Solar M. C., Woodward W. R. Iodine-123 metaiodobenzylguanidine imaging of the heart in idiopathic congestive cardiomyopathy and cardiac transplants. J Nucl Med. 1989 Jul;30(7):1182–1191. [PubMed] [Google Scholar]
  18. Hasking G. J., Esler M. D., Jennings G. L., Burton D., Johns J. A., Korner P. I. Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation. 1986 Apr;73(4):615–621. doi: 10.1161/01.cir.73.4.615. [DOI] [PubMed] [Google Scholar]
  19. Kienzle M. G., Ferguson D. W., Birkett C. L., Myers G. A., Berg W. J., Mariano D. J. Clinical, hemodynamic and sympathetic neural correlates of heart rate variability in congestive heart failure. Am J Cardiol. 1992 Mar 15;69(8):761–767. doi: 10.1016/0002-9149(92)90502-p. [DOI] [PubMed] [Google Scholar]
  20. Leimbach W. N., Jr, Wallin B. G., Victor R. G., Aylward P. E., Sundlöf G., Mark A. L. Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Circulation. 1986 May;73(5):913–919. doi: 10.1161/01.cir.73.5.913. [DOI] [PubMed] [Google Scholar]
  21. Levine T. B., Francis G. S., Goldsmith S. R., Simon A. B., Cohn J. N. Activity of the sympathetic nervous system and renin-angiotensin system assessed by plasma hormone levels and their relation to hemodynamic abnormalities in congestive heart failure. Am J Cardiol. 1982 May;49(7):1659–1666. doi: 10.1016/0002-9149(82)90243-0. [DOI] [PubMed] [Google Scholar]
  22. Mann D. L., Kent R. L., Parsons B., Cooper G., 4th Adrenergic effects on the biology of the adult mammalian cardiocyte. Circulation. 1992 Feb;85(2):790–804. doi: 10.1161/01.cir.85.2.790. [DOI] [PubMed] [Google Scholar]
  23. Melon P. G., Nguyen N., DeGrado T. R., Mangner T. J., Wieland D. M., Schwaiger M. Imaging of cardiac neuronal function after cocaine exposure using carbon-11 hydroxyephedrine and positron emission tomography. J Am Coll Cardiol. 1994 Jun;23(7):1693–1699. doi: 10.1016/0735-1097(94)90677-7. [DOI] [PubMed] [Google Scholar]
  24. Meredith I. T., Broughton A., Jennings G. L., Esler M. D. Evidence of a selective increase in cardiac sympathetic activity in patients with sustained ventricular arrhythmias. N Engl J Med. 1991 Aug 29;325(9):618–624. doi: 10.1056/NEJM199108293250905. [DOI] [PubMed] [Google Scholar]
  25. Meredith I. T., Eisenhofer G., Lambert G. W., Dewar E. M., Jennings G. L., Esler M. D. Cardiac sympathetic nervous activity in congestive heart failure. Evidence for increased neuronal norepinephrine release and preserved neuronal uptake. Circulation. 1993 Jul;88(1):136–145. doi: 10.1161/01.cir.88.1.136. [DOI] [PubMed] [Google Scholar]
  26. Merlet P., Valette H., Dubois-Randé J. L., Moyse D., Duboc D., Dove P., Bourguignon M. H., Benvenuti C., Duval A. M., Agostini D. Prognostic value of cardiac metaiodobenzylguanidine imaging in patients with heart failure. J Nucl Med. 1992 Apr;33(4):471–477. [PubMed] [Google Scholar]
  27. Mitrani R. D., Klein L. S., Miles W. M., Hackett F. K., Burt R. W., Wellman H. N., Zipes D. P. Regional cardiac sympathetic denervation in patients with ventricular tachycardia in the absence of coronary artery disease. J Am Coll Cardiol. 1993 Nov 1;22(5):1344–1353. doi: 10.1016/0735-1097(93)90541-8. [DOI] [PubMed] [Google Scholar]
  28. Mélon P., Schwaiger M. Imaging of metabolism and autonomic innervation of the heart by positron emission tomography. Eur J Nucl Med. 1992;19(6):453–464. doi: 10.1007/BF00177375. [DOI] [PubMed] [Google Scholar]
  29. Port J. D., Gilbert E. M., Larrabee P., Mealey P., Volkman K., Ginsburg R., Hershberger R. E., Murray J., Bristow M. R. Neurotransmitter depletion compromises the ability of indirect-acting amines to provide inotropic support in the failing human heart. Circulation. 1990 Mar;81(3):929–938. doi: 10.1161/01.cir.81.3.929. [DOI] [PubMed] [Google Scholar]
  30. Rabinovitch M. A., Rose C. P., Rouleau J. L., Chartrand C., Wieland D. M., Lepanto L., Legault F., Suissa S., Rosenthall L., Burgess J. H. Metaiodobenzylguanidine [131I] scintigraphy detects impaired myocardial sympathetic neuronal transport function of canine mechanical-overload heart failure. Circ Res. 1987 Dec;61(6):797–804. doi: 10.1161/01.res.61.6.797. [DOI] [PubMed] [Google Scholar]
  31. Rose C. P., Burgess J. H., Cousineau D. Reduced aortocoronary sinus extraction of epinephrine in patients with left ventricular failure secondary to long-term pressure or volume overload. Circulation. 1983 Aug;68(2):241–244. doi: 10.1161/01.cir.68.2.241. [DOI] [PubMed] [Google Scholar]
  32. Rose C. P., Burgess J. H., Cousineau D. Tracer norepinephrine kinetics in coronary circulation of patients with heart failure secondary to chronic pressure and volume overload. J Clin Invest. 1985 Nov;76(5):1740–1747. doi: 10.1172/JCI112164. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Rosenspire K. C., Haka M. S., Van Dort M. E., Jewett D. M., Gildersleeve D. L., Schwaiger M., Wieland D. M. Synthesis and preliminary evaluation of carbon-11-meta-hydroxyephedrine: a false transmitter agent for heart neuronal imaging. J Nucl Med. 1990 Aug;31(8):1328–1334. [PubMed] [Google Scholar]
  34. Rundqvist B., Elam M., Bergmann-Sverrisdottir Y., Eisenhofer G., Friberg P. Increased cardiac adrenergic drive precedes generalized sympathetic activation in human heart failure. Circulation. 1997 Jan 7;95(1):169–175. doi: 10.1161/01.cir.95.1.169. [DOI] [PubMed] [Google Scholar]
  35. Schofer J., Spielmann R., Schuchert A., Weber K., Schlüter M. Iodine-123 meta-iodobenzylguanidine scintigraphy: a noninvasive method to demonstrate myocardial adrenergic nervous system disintegrity in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1988 Nov;12(5):1252–1258. doi: 10.1016/0735-1097(88)92608-3. [DOI] [PubMed] [Google Scholar]
  36. Schwaiger M., Guibourg H., Rosenspire K., McClanahan T., Gallagher K., Hutchins G., Wieland D. M. Effect of regional myocardial ischemia on sympathetic nervous system as assessed by fluorine-18-metaraminol. J Nucl Med. 1990 Aug;31(8):1352–1357. [PubMed] [Google Scholar]
  37. Schwaiger M., Hutchins G. D., Kalff V., Rosenspire K., Haka M. S., Mallette S., Deeb G. M., Abrams G. D., Wieland D. Evidence for regional catecholamine uptake and storage sites in the transplanted human heart by positron emission tomography. J Clin Invest. 1991 May;87(5):1681–1690. doi: 10.1172/JCI115185. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Schwaiger M., Kalff V., Rosenspire K., Haka M. S., Molina E., Hutchins G. D., Deeb M., Wolfe E., Jr, Wieland D. M. Noninvasive evaluation of sympathetic nervous system in human heart by positron emission tomography. Circulation. 1990 Aug;82(2):457–464. doi: 10.1161/01.cir.82.2.457. [DOI] [PubMed] [Google Scholar]
  39. Schömig A., Dart A. M., Dietz R., Mayer E., Kübler W. Release of endogenous catecholamines in the ischemic myocardium of the rat. Part A: Locally mediated release. Circ Res. 1984 Nov;55(5):689–701. doi: 10.1161/01.res.55.5.689. [DOI] [PubMed] [Google Scholar]
  40. Schömig A., Fischer S., Kurz T., Richardt G., Schömig E. Nonexocytotic release of endogenous noradrenaline in the ischemic and anoxic rat heart: mechanism and metabolic requirements. Circ Res. 1987 Feb;60(2):194–205. doi: 10.1161/01.res.60.2.194. [DOI] [PubMed] [Google Scholar]
  41. Simmons W. W., Freeman M. R., Grima E. A., Hsia T. W., Armstrong P. W. Abnormalities of cardiac sympathetic function in pacing-induced heart failure as assessed by [123I]metaiodobenzylguanidine scintigraphy. Circulation. 1994 Jun;89(6):2843–2851. doi: 10.1161/01.cir.89.6.2843. [DOI] [PubMed] [Google Scholar]
  42. Swedberg K., Eneroth P., Kjekshus J., Wilhelmsen L. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. CONSENSUS Trial Study Group. Circulation. 1990 Nov;82(5):1730–1736. doi: 10.1161/01.cir.82.5.1730. [DOI] [PubMed] [Google Scholar]
  43. Takatsu H., Uno Y., Fujiwara H. Modulation of left ventricular iodine-125-MIBG accumulation in cardiomyopathic Syrian hamsters using the renin-angiotensin system. J Nucl Med. 1995 Jun;36(6):1055–1061. [PubMed] [Google Scholar]
  44. Zipes D. P. Influence of myocardial ischemia and infarction on autonomic innervation of heart. Circulation. 1990 Oct;82(4):1095–1105. doi: 10.1161/01.cir.82.4.1095. [DOI] [PubMed] [Google Scholar]
  45. Zipes D. P. Sympathetic stimulation and arrhythmias. N Engl J Med. 1991 Aug 29;325(9):656–657. doi: 10.1056/NEJM199108293250911. [DOI] [PubMed] [Google Scholar]

Articles from Heart are provided here courtesy of BMJ Publishing Group

RESOURCES