Abstract
In recent years, the importance of alterations of cardiac autonomic nerve function in the pathophysiology of heart diseases including heart failure, arrhythmia, ischemic heart disease, and diabetes has been increasingly recognized. Several radiolabeled compounds have been synthesized for noninvasive imaging, including single photon emission CT and positron emission tomography (PET). The catecholamine analogue I-123 metaiodobenzylguanidine (MIBG) is the most commonly used tracer for mapping of myocardial presynaptic sympathetic innervation on a broad clinical basis. In addition, radiolabeled catecholamines and catecholamine analogues are available for PET imaging, which allows absolute quantification and tracer kinetics modeling. Postsynaptic receptor PET imaging added new insights into mechanisms of heart disease. These advanced imaging techniques provide noninvasive, repeatable in vivo information of autonomic nerve function in the human heart and are promising for providing profound insights into molecular pathophysiology, monitoring of treatment, and determination of individual outcome.
Article PDF
Similar content being viewed by others
Explore related subjects
Discover the latest articles, news and stories from top researchers in related subjects.Avoid common mistakes on your manuscript.
References and Recommended Reading
Fukuda N, Granzier H: Role of the giant elastic protein titin in the Frank-Starling mechanism of the heart. Curr Vasc Pharmacol 2004, 2:135–139.
Kaye D, Esler M: Sympathetic neuronal regulation of the heart in aging and heart failure. Cardiovasc Res 2005, 66:256–264.
Chatterjee K: Neurohormonal activation in congestive heart failure and the role of vasopressin. Am J Cardiol 2005, 95:8B-13B.
Yen CT, Hwang JC, Su CK, et al.: Differential actions of the medial region of caudal medulla on autonomic nerve activities. Clin Exp Pharmacol Physiol 1991, 18:743–751.
Levy MN: Cardiac sympathetic-parasympathetic interactions. Fed Proc 1984, 43:2598–2602.
Eisenhofer G, Kopin IJ, Goldstein DS: Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacol Rev 2004, 56:331–349.
Goldstein DS, Brush JE Jr, Eisenhofer G, et al.: In vivo measurement of neuronal uptake of norepinephrine in the human heart. Circulation 1988, 78:41–48.
Clarke DE, Jones CJ, Linley PA: Histochemical fluorescence studies on noradrenaline accumulation by Uptake 2 in the isolated rat heart. Br J Pharmacol 1969, 37:1–9.
Hasking GJ, Esler MD, Jennings GL, et al.: Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation 1986, 73:615–621.
Hein L, Altman JD, Kobilka BK: Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission. Nature 1999, 402:181–184.
Raffel DM, Wieland DM: Assessment of cardiac sympathetic nerve integrity with positron emission tomography. Nucl Med Biol 2001, 28:541–559.
Paton WD, Vizi ES, Zar MA: The mechanism of acetylcholine release from parasympathetic nerves. J Physiol 1971, 215:819–848.
Harvey RD, Belevych AE: Muscarinic regulation of cardiac ion channels. Br J Pharmacol 2003, 139:1074–1084.
Tseng H, Link JM, Stratton JR, et al.: Cardiac receptor physiology and its application to clinical imaging: present and future. J Nucl Cardiol 2001, 8:390–409.
Carrio I: Cardiac neurotransmission imaging. J Nucl Med 2001, 42:1062–1076.
Langer O, Halldin C: PET and SPET tracers for mapping the cardiac nervous system. Eur J Nucl Med Mol Imaging 2002, 29:416–434.
Knuuti J, Sipola P: Is it time for cardiac innervation imaging? Q J Nucl Med Mol Imaging 2005, 49:97–105.
Flotats A, Carrio I: Cardiac neurotransmission SPECT imaging. J Nucl Cardiol 2004, 11:587–602.
Bengel FM, Schwaiger M: Assessment of cardiac sympathetic neuronal function using PET imaging. J Nucl Cardiol 2004, 11:603–616.
Wieland DM, Brown LE, Rogers WL, et al.: Myocardial imaging with a radioiodinated norepinephrine storage analog. J Nucl Med 1981, 22:22–31.
Patel AD, Iskandrian AE: MIBG imaging. J Nucl Cardiol 2002, 9:75–94.
Schomig A, Fischer S, Kurz T, et al.: Nonexocytotic release of endogenous noradrenaline in the ischemic and anoxic rat heart: mechanism and metabolic requirements. Circ Res 1987, 60:194–205.
Dae MW, De Marco T, Botvinick EH, et al.: Scintigraphic assessment of MIBG uptake in globally denervated human and canine hearts--implications for clinical studies. J Nucl Med 1992, 33:1444–1450.
Glowniak JV, Turner FE, Gray LL, et al.: Iodine-123 metaiodobenzylguanidine imaging of the heart in idiopathic congestive cardiomyopathy and cardiac transplants. J Nucl Med 1989, 30:1182–1191.
Nishimura T, Sugishita Y, Sasaki Y: [The results of questionnaire on quantitative assessment of 123Imetaiodobenzylguanidine myocardial scintigraphy in heart failure]. Kaku Igaku 1997, 34:1139–1148.
Melon P, Schwaiger M: Imaging of metabolism and autonomic innervation of the heart by positron emission tomography. Eur J Nucl Med 1992, 19:453–464.
Raffel DM, Corbett JR, del Rosario RB, et al.: Clinical evaluation of carbon-11-phenylephrine: MAO-sensitive marker of cardiac sympathetic neurons. J Nucl Med 1996, 37:1923–1931.
Munch G, Nguyen NT, Nekolla S, et al.: Evaluation of sympathetic nerve terminals with [(11)C]epinephrine and [(11)C]hydroxyephedrine and positron emission tomography. Circulation 2000, 101:516–523.
Del Rosario RB, Jung YW, Caraher J, et al.: Synthesis and preliminary evaluation of [11C]-(-)-phenylephrine as a functional heart neuronal PET agent. Nucl Med Biol 1996, 23:611–616.
de Jong RM, Blanksma PK, van Waarde A, et al.: Measurement of myocardial beta-adrenoceptor density in clinical studies: a role for positron emission tomography? Eur J Nucl Med Mol Imaging 2002, 29:88–97.
Law MP: Demonstration of the suitability of CGP 12177 for in vivo studies of beta-adrenoceptors. Br J Pharmacol 1993, 109:1101–1109.
Delforge J, Mesangeau D, Dolle F, et al.: In vivo quantification and parametric images of the cardiac beta-adrenergic receptor density. J Nucl Med 2002, 43:215–226.
Elsinga PH, van Waarde A, Jaeggi KA, et al.: Synthesis and evaluation of (S)-4-(3-(2'-[11C]isopropylamino)-2-hydroxypropoxy) -2H-benzimidazol -2-one ((S)-[11C]CGP 12388) and (S)-4-(3-((1'-[18F]-.uoroisopropyl)amino)-2-hydroxypropoxy)-2H-benzimidazol-2-one ((S)-[18F].uoro-CGP 12388) for visualization of betaadrenoceptors with positron emission tomography. J Med Chem 1997, 40:3829–3835.
Momose M, Reder S, Raffel DM, et al.: Evaluation of cardiac beta-adrenoreceptors in the isolated perfused rat heart using (S)-11C-CGP12388. J Nucl Med 2004, 45:471–477.
Doze P, Elsinga PH, van Waarde A, et al.: 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 2002, 29:295–304.
DeGrado TR, Mulholland GK, Wieland DM, et al.: Evaluation of (-)[18F].uoroethoxybenzovesamicol as a new PET tracer of cholinergic neurons of the heart. Nucl Med Biol 1994, 21:189–195.
Kassiou M, Mardon K, Katsifis AG, et al.: Radiosynthesis of [123I]N-methyl-4-iododexetimide and [123I]N-methyl-4-iodolevetimide: in vitro and in vivo characterisation of binding to muscarinic receptors in the rat heart. Nucl Med Biol 1996, 23:147–153.
Syrota A, Comar D, Paillotin G, et al.: Muscarinic cholinergic receptor in the human heart evidenced under physiological conditions by positron emission tomography. Proc Natl Acad Sci U S A 1985, 82:584–588.
Valette H, Syrota A, Fuseau C: Down-regulation of cardiac muscarinic receptors induced by di-isopropylfluorophosphate. J Nucl Med 1997, 38:1430–1433.
Lovric SS, Avbelj V, Trobec R, et al.: Sympathetic reinnervation after heart transplantation, assessed by iodine-123 metaiodobenzylguanidine imaging, and heart rate variability. Eur J Cardiothorac Surg 2004, 26:736–741.
Estorch M, Camprecios M, Flotats A, et al.: Sympathetic reinnervation of cardiac allografts evaluated by 123IMIBG imaging. J Nucl Med 1999, 40:911–916.
Bengel FM, Ueberfuhr P, Hesse T, et al.: Clinical determinants of ventricular sympathetic reinnervation after orthotopic heart transplantation. Circulation 2002, 106:831–835.
Bengel FM, Ueberfuhr P, Ziegler SI, et al.: Serial assessment of sympathetic reinnervation after orthotopic heart transplantation. A longitudinal study using PET and C-11 hydroxyephedrine. Circulation 1999, 99:1866–1871.
Schwaiger M, Hutchins GD, Kalff V, et al.: Evidence for regional catecholamine uptake and storage sites in the transplanted human heart by positron emission tomography. J Clin Invest 1991, 87:1681–1690.
Bengel FM, Ueberfuhr P, Schiepel N, et al.: Effect of sympathetic reinnervation on cardiac performance after heart transplantation. N Engl J Med 2001, 345:731–738.
Bengel FM, Ueberfuhr P, Ziegler SI, et al.: Non-invasive assessment of the effect of cardiac sympathetic innervation on metabolism of the human heart. Eur J Nucl Med 2000, 27:1650–1657.
Di Carli MF, Tobes MC, Mangner T, et al.: Effects of cardiac sympathetic innervation on coronary blood flow. N Engl J Med 1997, 336:1208–1215.
Stevens MJ, Raffel DM, Allman KC, et al.: Cardiac sympathetic dysinnervation in diabetes: implications for enhanced cardiovascular risk. Circulation 1998, 98:961–968.
Hattori N, Tamaki N, Hayashi T, et al.: Regional abnormality of iodine-123-MIBG in diabetic hearts. J Nucl Med 1996, 37:1985–1990.
Kiyono Y, Kajiyama S, Fujiwara H, et al.: Influence of the polyol pathway on norepinephrine transporter reduction in diabetic cardiac sympathetic nerves: implications for heterogeneous accumulation of MIBG. Eur J Nucl Med Mol Imaging 2005, 32:438–442.
Di Carli MF, Bianco-Batlles D, Landa ME, et al.: Effects of autonomic neuropathy on coronary blood flow in patients with diabetes mellitus. Circulation 1999, 100:813–819.
Schwaiger M, Guibourg H, Rosenspire K, et al.: Effect of regional myocardial ischemia on sympathetic nervous system as assessed by fluorine-18-metaraminol. J Nucl Med 1990, 31:1352–1357.
Nakajima K, Shuke N, Nitta Y, et al.: Comparison of 99Tcm-pyrophosphate, 201T1 perfusion, 123I-labelled methyl-branched fatty acid and sympathetic imaging in acute coronary syndrome. Nucl Med Commun 1995, 16:494–503.
Tomoda H, Yoshioka K, Shiina Y, et al.: Regional sympathetic denervation detected by iodine 123 metaiodobenzylguanidine in non-Q-wave myocardial infarction and unstable angina. Am Heart J 1994, 128:452–458.
Minardo JD, Tuli MM, Mock BH, et al.: Scintigraphic and electrophysiological evidence of canine myocardial sympathetic denervation and reinnervation produced by myocardial infarction or phenol application. Circulation 1988, 78:1008–1019.
Matsunari I, Schricke U, Bengel FM, et al.: Extent of cardiac sympathetic neuronal damage is determined by the area of ischemia in patients with acute coronary syndromes. Circulation 2000, 101:2579–2585.
Kasama S, Toyama T, Kumakura H, et al.: Effects of nicorandil on cardiac sympathetic nerve activity after reperfusion therapy in patients with first anterior acute myocardial infarction. Eur J Nucl Med Mol Imaging 2005, 32:322–328.
Ungerer M, Weig HJ, Kubert S, et al.: Regional pre- and postsynaptic sympathetic system in the failing human heart--regulation of beta ARK-1. Eur J Heart Fail 2000, 2:23–31.
Ungerer M, Hartmann F, Karoglan M, et al.: Regional in vivo and in vitro characterization of autonomic innervation in cardiomyopathic human heart. Circulation 1998, 97:174–180.
Merlet P, Valette H, Dubois-Rande JL, et al.: Prognostic value of cardiac metaiodobenzylguanidine imaging in patients with heart failure. J Nucl Med 1992, 33:471–477.
Kyuma M, Nakata T, Hashimoto A, et al.: Incremental prognostic implications of brain natriuretic peptide, cardiac sympathetic nerve innervation, and noncardiac disorders in patients with heart failure. J Nucl Med 2004, 45:155–163.
Nakata T, Wakabayashi T, Kyuma M, et al.: Cardiac metaiodobenzylguanidine activity can predict the long-term efficacy of angiotensin-converting enzyme inhibitors and/or beta-adrenoceptor blockers in patients with heart failure. Eur J Nucl Med Mol Imaging 2005, 32:186–194. This study demonstrated that the reduction of mortality risk with medical therapy in heart failure patients was associated with the severity of impairment of myocardial MIBG uptake.
Zipes DP, Wellens HJ: Sudden cardiac death. Circulation 1998, 98:2334–2351.
Tomaselli GF, Zipes DP: What causes sudden death in heart failure? Circ Res 2004, 95:754–763.
Bristow MR, Saxon LA, Boehmer J, et al.: Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004, 350:2140–2150.
Corsello A: An implantable cardioverter-defibrillator but not amiodarone reduced risk for death in congestive heart failure. ACP J Club 2005, 143:6.
Arora R, Ferrick KJ, Nakata T, et al.: I-123 MIBG imaging and heart rate variability analysis to predict the need for an implantable cardioverter defibrillator. J Nucl Cardiol 2003, 10:121–131. This study demonstrated that a combination of cardiac sympathetic nerve imaging and heart rate variability analysis may helps to select appropriate patients for an implantable defibillator therapy.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Higuchi, T., Schwaiger, M. Imaging cardiac neuronal function and dysfunction. Curr Cardiol Rep 8, 131–138 (2006). https://doi.org/10.1007/s11886-006-0024-z
Issue Date:
DOI: https://doi.org/10.1007/s11886-006-0024-z