Myocardial Presynaptic and Postsynaptic Autonomic Dysfunction in Hypertrophic Cardiomyopathy

From the MRC Cyclotron Unit and Imperial College School of Medicine (D.D., C.G.R., A.A.L., F.H., P.G.C.), Hammersmith Hospital, London, UK, and the Department of Nuclear Medicine (M.S., O.S.), University of Münster (Germany).

Correspondence to Paolo G. Camici, MD, MRC Cyclotron Unit, Hammersmith Hospital, Ducane Road, London W12 ONN, UK. E-mail paolo{at}cu.rpms.ac.uk

Abstract—Although hypertrophic cardiomyopathy (HCM) is genetically determined, several other factors, including autonomic dysfunction, may play a role in the phenotypic expression. A recent study using positron emission tomography with [¹¹C]CGP 12177 ([¹¹C]CGP) demonstrated that ß-adrenoceptor (ßAR) density is reduced in HCM and is correlated with disease progression. This present study tested the hypothesis that this downregulation is associated with reduced catecholamine reuptake (uptake 1) by myocardial sympathetic nerve terminals leading to increased local norepinephrine concentration. Myocardial presynaptic catecholamine reuptake was assessed by measuring the volume of distribution (V_d) of the catecholamine analogue [¹¹C]hydroxyephedrine ([¹¹C]HED) in 9 unrelated HCM patients aged 45±15 years. The maximum number of binding sites (B_max) for myocardial ßAR density was measured in 13 unrelated HCM patients aged 40±12 years using the nonselective ß blocker [¹¹C]CGP. Six patients were studied with both [¹¹C]HED and [¹¹C]CGP. Comparison was made with two groups of healthy control subjects for each ligand ([¹¹C]HED, n=10, aged 35±8 years; [¹¹C]CGP, n=19, aged 44±16 years). Myocardial V_d of [¹¹C]HED (33.4±4.3 mL/g tissue) and ßAR density (7.3±2.6 pmol/g tissue) were significantly reduced in HCM patients compared with control subjects (71.0±18.8 mL/g tissue, P<.001, and 10.2±2.9 pmol/g tissue, P=.008, respectively). These results are consistent with our hypothesis that myocardial ßAR downregulation in HCM is associated with an impaired uptake-1 mechanism and hence increased local catecholamine levels.

Key Words: cardiomyopathy, hypertrophic • autonomic dysfunction • catecholamines • beta adrenoceptors • positron emission tomography

This article has been cited by other articles:

				C. M. Prado, E. J. Fine, W. Koba, D. Zhao, M. A. Rossi, H. B. Tanowitz, and L. A. Jelicks Micro-Positron Emission Tomography in the Evaluation of Trypanosoma cruzi-Induced Heart Disease: Comparison with Other Modalities Am J Trop Med Hyg, November 1, 2009; 81(5): 900 - 905. [Abstract] [Full Text] [PDF]

				J. H. Caldwell, J. M. Link, W. C. Levy, J. E. Poole, and J. R. Stratton Evidence for Pre- to Postsynaptic Mismatch of the Cardiac Sympathetic Nervous System in Ischemic Congestive Heart Failure J. Nucl. Med., February 1, 2008; 49(2): 234 - 241. [Abstract] [Full Text] [PDF]

				T. Tsukamoto, K. Morita, M. Naya, M. Inubushi, C. Katoh, K. Nishijima, Y. Kuge, H. Okamoto, H. Tsutsui, and N. Tamaki Decreased Myocardial {beta}-Adrenergic Receptor Density in Relation to Increased Sympathetic Tone in Patients with Nonischemic Cardiomyopathy J. Nucl. Med., November 1, 2007; 48(11): 1777 - 1782. [Abstract] [Full Text] [PDF]

				J J Bax, R S Beanlands, F J Klocke, J Knuuti, A A Lammertsma, M A Schaefers, H R Schelbert, G K Von Schulthess, L J Shaw, G Z Yang, et al. Diagnostic and clinical perspectives of fusion imaging in cardiology: is the total greater than the sum of its parts? Heart, January 1, 2007; 93(1): 16 - 22. [Abstract] [Full Text] [PDF]

				S. F. Nagueh and J. J. Mahmarian Noninvasive Cardiac Imaging in Patients With Hypertrophic Cardiomyopathy J. Am. Coll. Cardiol., December 19, 2006; 48(12): 2410 - 2422. [Abstract] [Full Text] [PDF]

				S. R. Ommen There Is Much More to the Recipe Than Just Outflow Obstruction J. Am. Coll. Cardiol., October 18, 2005; 46(8): 1551 - 1552. [Full Text] [PDF]

				M. Schwaiger, S. Ziegler, and S. G. Nekolla PET/CT: Challenge for Nuclear Cardiology J. Nucl. Med., October 1, 2005; 46(10): 1664 - 1678. [Abstract] [Full Text] [PDF]

				L. Stegger, K. P. Schafers, U. Flogel, L. Livieratos, S. Hermann, C. Jacoby, P. Keul, E. M. Conway, O. Schober, J. Schrader, et al. Monitoring Left Ventricular Dilation in Mice with PET J. Nucl. Med., September 1, 2005; 46(9): 1516 - 1521. [Abstract] [Full Text] [PDF]

				S. Isobe, H. Izawa, M. Iwase, M. Nanasato, M. Nonokawa, A. Ando, S. Ohshima, K. Nagata, K. Kato, T. Nishizawa, et al. Cardiac 123I-MIBG Reflects Left Ventricular Functional Reserve in Patients with Nonobstructive Hypertrophic Cardiomyopathy J. Nucl. Med., June 1, 2005; 46(6): 909 - 916. [Abstract] [Full Text] [PDF]

				P. Kies, T. Wichter, M. Schafers, M. Paul, K. P. Schafers, L. Eckardt, L. Stegger, E. Schulze-Bahr, O. Rimoldi, G. Breithardt, et al. Abnormal Myocardial Presynaptic Norepinephrine Recycling in Patients With Brugada Syndrome Circulation, November 9, 2004; 110(19): 3017 - 3022. [Abstract] [Full Text] [PDF]

				M. Jorg-Ciopor, M. Namdar, J. Turina, R. Jenni, J. Schwitter, M. Turina, O. M. Hess, and P. A. Kaufmann Regional myocardial ischemia in hypertrophic cardiomyopathy: Impact of myectomy J. Thorac. Cardiovasc. Surg., August 1, 2004; 128(2): 163 - 169. [Abstract] [Full Text] [PDF]

				M. Momose, S. Reder, D. M. Raffel, P. Watzlowik, H.-J. Wester, N. Nguyen, P. H. Elsinga, F. M. Bengel, J. Remien, and M. Schwaiger Evaluation of Cardiac {beta}-Adrenoreceptors in the Isolated Perfused Rat Heart Using (S)-11C-CGP12388 J. Nucl. Med., March 1, 2004; 45(3): 471 - 477. [Abstract] [Full Text]

				H. Terai, M. Shimizu, H. Ino, M. Yamaguchi, K. Uchiyama, K. Oe, K. Nakajima, J. Taki, M. Kawano, and H. Mabuchi Changes in Cardiac Sympathetic Nerve Innervation and Activity in Pathophysiologic Transition from Typical to End-Stage Hypertrophic Cardiomyopathy J. Nucl. Med., October 1, 2003; 44(10): 1612 - 1617. [Abstract] [Full Text] [PDF]

				K. Mardon, O. Montagne, N. Elbaz, Z. Malek, A. Syrota, J.-L. Dubois-Rande, M. Meignan, and P. Merlet Uptake-1 Carrier Downregulates in Parallel with the {beta}-Adrenergic Receptor Desensitization in Rat Hearts Chronically Exposed to High Levels of Circulating Norepinephrine: Implications for Cardiac Neuroimaging in Human Cardiomyopathies J. Nucl. Med., September 1, 2003; 44(9): 1459 - 1466. [Abstract] [Full Text] [PDF]

				P. Sipola, E. Vanninen, H. J. Aronen, K. Lauerma, S. Simula, P. Jaaskelainen, M. Laakso, K. Peuhkurinen, J. Kuusisto, and J. T. Kuikka Cardiac Adrenergic Activity Is Associated with Left Ventricular Hypertrophy in Genetically Homogeneous Subjects with Hypertrophic Cardiomyopathy J. Nucl. Med., April 1, 2003; 44(4): 487 - 493. [Abstract] [Full Text] [PDF]

				N. Spyrou, S. D. Rosen, F. Fath-Ordoubadi, R. Jagathesan, R. Foale, J. S. Kooner, and P. G. Camici Myocardial beta-adrenoceptor densityone month after acute myocardial infarctionpredicts left ventricular volumes at six months J. Am. Coll. Cardiol., October 2, 2002; 40(7): 1216 - 1224. [Abstract] [Full Text] [PDF]

				P G Camici Imaging of cardiac adrenergic innervation Heart, September 1, 2002; 88(3): 209 - 210. [Full Text] [PDF]

				J. L. Lavoie, A. Calderone, and L. Beliveau A farnesyltransferase inhibitor attenuated beta -adrenergic receptor downregulation in rat skeletal muscle Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2002; 282(1): R317 - R322. [Abstract] [Full Text] [PDF]

				K. Freeman, C. Colon-Rivera, M. C. Olsson, R. L. Moore, H. D. Weinberger, I. L. Grupp, K. L. Vikstrom, G. Iaccarino, W. J. Koch, and L. A. Leinwand Progression from hypertrophic to dilated cardiomyopathy in mice that express a mutant myosin transgene Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H151 - H159. [Abstract] [Full Text] [PDF]

				S.-T. Li, C. J. Tack, L. Fananapazir, and D. S. Goldstein Myocardial perfusion and sympathetic innervation in patients with hypertrophic cardiomyopathy J. Am. Coll. Cardiol., June 1, 2000; 35(7): 1867 - 1873. [Abstract] [Full Text] [PDF]

				T. Wichter, M. Schafers, C. G. Rhodes, M. Borggrefe, H. Lerch, A. A. Lammertsma, F. Hermansen, O. Schober, G. Breithardt, and P. G. Camici 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, April 4, 2000; 101(13): 1552 - 1558. [Abstract] [Full Text] [PDF]

				P. G Camici IMAGING TECHNIQUES: Positron emission tomography and myocardial imaging Heart, April 1, 2000; 83(4): 475 - 480. [Full Text]

				M. Schafers, H. Lerch, T. Wichter, C. G. Rhodes, A. A. Lammertsma, M. Borggrefe, F. Hermansen, O. Schober, G.u. Breithardt, and P. G. Camici Cardiac sympathetic innervation in patients with idiopathic right ventricular outflow tract tachycardia J. Am. Coll. Cardiol., July 1, 1998; 32(1): 181 - 186. [Abstract] [Full Text] [PDF]

				T. Wichter, P. Matheja, L. Eckardt, P. Kies, K. Schafers, E. Schulze-Bahr, W. Haverkamp, M. Borggrefe, O. Schober, G. Breithardt, et al. Cardiac Autonomic Dysfunction in Brugada Syndrome Circulation, February 12, 2002; 105(6): 702 - 706. [Abstract] [Full Text] [PDF]