Correspondence

Sympathetic Reinnervation of the Transplanted Heart

N Engl J Med 2001; 345:1914-1915December 27, 2001

Article

To the Editor:

The issue of whether there is sympathetic reinnervation in the transplanted human heart remains debatable. Bengel et al. (Sept. 6 issue)1 reported adrenergic activity in transplanted human hearts on the basis of the detection of the uptake of a catecholamine analogue by myocardium on positron-emission tomography. They claimed that sympathetic reinnervation occurred five years after heart transplantation and that the cardiac contractile response to exercise in patients with reinnervation was similar to that in normal controls. We question whether this cardiac adrenergic activity was indeed derived from the sympathetic reinnervation. If so, sympathetic nerve fibers would easily have been identified in the transplanted hearts at levels similar to normal. Yet, their study provided no histologic data to substantiate the presence of cardiac reinnervation. In fact, electron-microscopical analysis failed to identify the presence of sympathetic reinnervation in long-term (approximately 12 years) survivors of heart transplantation.2

It has been known for decades that the isolated animal heart can synthesize norepinephrine.3 More recently, we demonstrated that the mammalian heart contained intrinsic cardiac adrenergic cells possessing messenger RNA of tyrosine hydroxylase and tyrosine hydroxylase protein, the rate-limiting enzyme for catecholamine synthesis.4 Complete catecholamine-synthesizing enzymes, including tyrosine hydroxylase, dopamine β-hydroxylase, and phenylethanolamine N-methyltransferase, exist in intrinsic cardiac adrenergic cells. They can synthesize and constitutively release epinephrine and norepinephrine to regulate the contraction of myocytes in vitro. Moreover, intrinsic cardiac adrenergic cells are present in human fetal hearts before sympathetic innervation occurs.4 Recently, Singh et al.5 demonstrated that in the hearts of adults, cells associated with intrinsic cardiac ganglia had tyrosine hydroxylase, dopamine β-hydroxylase, and phenylethanolamine N-methyltransferase immunoreactivity. These cells produce dopamine and norepinephrine. Human intrinsic cardiac adrenergic cells may provide an alternative means of adrenergic support after sympathetic denervation in transplanted hearts.

Ming-He Huang, M.D., Ph.D.
Gordon A. Ewy, M.D.
University of Arizona, Tucson, AZ 85724-5037
mhuang1458@aol.com

5 References

1. 1

   Bengel FM, Ueberfuhr P, Schiepel N, Nekolla SG, Reichart B, Schwaiger M. Effect of sympathetic reinnervation on cardiac performance after heart transplantation. N Engl J Med 2001;345:731-738
   Full Text | Web of Science | Medline

2. 2

   Rowan RA, Billingham ME. Myocardial innervation in long-term heart transplant survivors: a quantitative ultrastructural survey. J Heart Transplant 1988;7:448-452
   Medline

3. 3

   Chidsey CA, Kaiser GA, Braunwald E. Biosynthesis of norepinephrine in isolated canine heart. Science 1963;139:828-829
   CrossRef | Web of Science | Medline

4. 4

   Huang MH, Friend DS, Sunday ME, et al. An intrinsic adrenergic system in mammalian heart. J Clin Invest 1996;98:1298-1303
   CrossRef | Web of Science | Medline

5. 5

   Singh S, Johnson PI, Javed A, Gray TS, Lonchyna VA, Wurster RD. Monoamine- and histamine-synthesizing enzymes and neurotransmitters within neurons of adult human cardiac ganglia. Circulation 1999;99:411-419
   Web of Science | Medline

To the Editor:

Bengel and colleagues showed that in heart-transplant recipients, the restoration of sympathetic reinnervation is associated with improved responses of heart rate and contractile function to exercise. It would be interesting to know which surgical technique was used to transplant the hearts. In fact, it has been reported that, as compared with the standard procedure of atrial anastomosis, the use of bicaval anastomosis increased sinus-rhythm recovery, decreased the frequency of atrial arrhythmias, and reduced mortality.1,2 These effects could be related to the preservation of an intracardiac autonomic network, leading to faster reinnervation and increased electrical stability.

Gianfranco Butera, M.D., Ph.D.
Istituto Policlinico San Donato, 20097 San Donato Milanese, Italy
gianfra.but@lycos.com

2 References

1. 1

   Singh S, Johnson PI, Lee RE, et al. Topography of cardiac ganglia in the adult human heart. J Thorac Cardiovasc Surg 1996;112:943-953
   CrossRef | Web of Science | Medline

2. 2

   el Gamel A, Yonan NA, Rahman AN, Deiraniya AK, Campbell CS, Sarsam MA. The clinical benefit of the bicaval technique for cardiac transplantation. J Thorac Cardiovasc Surg 1995;109:1257-1259
   CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: The hypothesis of Huang and Ewy that intrinsic mechanisms of the heart may contribute to adrenergic stimulation in denervated hearts is interesting. There are some data to support the presence of an intrinsic adrenergic system, but the extent of this system throughout ventricular myocardium is not well defined, and its contribution to the regulation of physiologic processes remains to be determined.

Regional myocardial uptake of [¹¹C]hydroxyephedrine is absent soon after heart transplantation, but it reappears and increases with time after transplantation, as demonstrated in longitudinal observations.1 Uptake is initially observed in the basal anterior wall of the left ventricle and then extends toward the septum and lateral wall, but it remains incomplete until late after surgery. This dynamic phenomenon and its independent correlation with enhanced exercise performance are unlikely to be explained by an intrinsic mechanism that remains unaffected by the transplantation procedure.

With respect to the regional appearance of reinnervation, it is not surprising that early histologic studies referred to by Huang and Ewy failed to identify nerve fibers after transplantation. The number of patients studied was small, and the biopsy samples were obtained from the right ventricle. Therefore, the area of reinnervation was most likely not included. In contrast, when left ventricular myocardium was assessed in a patient who died three months after positron-emission tomography, nerve fibers were detectable in the basal anterior wall (where the retention of [¹¹C]hydroxyephedrine had been observed), but not in apical myocardium, thus providing histologic confirmation of the imaging results.2

A number of studies provide evidence that supports the specificity of [¹¹C]hydroxyephedrine for sympathetic nerve terminals and thus the validity of positron-emission tomography for the detection of reinnervation in heart transplants. Experimental studies of the neuronal-uptake inhibitor desipramine in rat hearts indicate that there is little extraneuronal distribution and that clearance of the tracer is strongly dependent on neuronal reuptake.3 In addition, there was a correlation between in vivo measurements of cardiac retention of [¹¹C]hydroxyephedrine in failing hearts before transplantation and in vitro measurements of the uptake – 1 carrier density (which is responsible for presynaptic catecholamine uptake) after explantation.4 And finally, the reappearance of cardiac [¹¹C]hydroxyephedrine uptake in transplant recipients was correlated with the reappearance of pharmacologically inducible transcardiac norepinephrine spillover late after transplantation.5

All our patients underwent standard transplantation with atrial anastomosis. We agree with Butera that the surgical approach may be one of several factors that influence the regrowth of nerves, which should be further investigated for an improved understanding of the reinnervation process.

Frank M. Bengel, M.D.
Technischen Universität München, 81675 Munich, Germany
frank.bengel@lrz.tu-muenchen.de

Peter Ueberfuhr, M.D.
Ludwig-Maximilians Universität München, 80539 Munich, Germany

Markus Schwaiger, M.D.
Technischen Universität München, 81675 Munich, Germany

5 References

1. 1

   Bengel FM, Ueberfuhr P, Ziegler SI, Nekolla S, Reichart B, Schwaiger M. Serial assessment of sympathetic reinnervation after orthotopic heart transplantation: a longitudinal study using PET and C-11 hydroxyephedrine. Circulation 1999;99:1866-1871
   Web of Science | Medline

2. 2

   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
   CrossRef | Web of Science | Medline

3. 3

   DeGrado TR, Hutchins GD, Toorongian SA, Wieland DM, Schwaiger M. Myocardial kinetics of carbon-11-meta-hydroxyephedrine: retention mechanisms and effects of norepinephrine. J Nucl Med 1993;34:1287-1293
   Web of Science | Medline

4. 4

   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
   Web of Science | Medline

5. 5

   Odaka K, von Scheidt W, Ziegler SI, et al. Reappearance of cardiac presynaptic sympathetic nerve terminals in the transplanted heart: correlation between PET using (11)C-hydroxyephedrine and invasively measured norepinephrine release. J Nucl Med 2001;42:1011-1016
   Web of Science | Medline

Citing Articles (1)

Citing Articles

1. 1

   Dave T. Kim, Daniel J. Luthringer, Angela C. Lai, Gina Suh, Lawrence Czer, Lan S. Chen, Peng-Sheng Chen, Michael C. Fishbein. (2004) Sympathetic nerve sprouting after orthotopic heart transplantation. The Journal of Heart and Lung Transplantation 23:12, 1349-1358
   CrossRef