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'Sick But Not Dead': Multiple Denervation-Independent Abnormalities of Myocardial Noradrenergic Function in Lewy Body Diseases

44 Pages Posted: 6 May 2019

See all articles by David S. Goldstein

David S. Goldstein

Government of the United States of America - Autonomic Medicine Section (formerly Clinical Neurocardiology Section

Mark Pekker

University of Alabama at Huntsville

Graeme Eisenhofer

Dresden University of Technology

Yehonatan Sharabi

Tel Aviv University - Sackler Faculty of Medicine

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Abstract

Background: Lewy body diseases such as Parkinson disease (PD) are well known to be characterized by nigrostriatal dopamine deficiency. These disorders also entail drastic (95-99%) myocardial depletion of the sympathetic neurotransmitter norepinephrine. Catecholamine loss in both regions cannot be accounted for by denervation alone. We evaluated the possibility of decreased innervation combined with functional abnormalities in residual nerves, using previously published data and a novel, comprehensive kinetic model. We then tested predictions from the model in new subject cohorts.

Methods: We calculated rate constants for 17 reactions related to myocardial intra-neuronal norepinephrine synthesis, storage, and disposition in control subjects and patients with Lewy body diseases. Post-mortem apical ventricular concentrations and concentration ratios of catechols were used to test predictions from the model in 11 controls and 11 patients with autopsy-proven PD.

Results: Calculated rate constants for vesicular storage of dopamine and norepinephrine, catecholamine biosynthesis via tyrosine hydroxylase and L-aromatic-amino-acid decarboxylase, and neuronal norepinephrine reuptake via the cell membrane norepinephrine transporter were reduced in the Lewy body group. In PD myocardial norepinephrine content was decreased by 99% from controls (p<0.0001). Post-mortem catechols and catechol ratios in PD patients confirmed the pattern of model-predicted functional abnormalities.

Conclusions: Denervation-independent impaired neurotransmitter biosynthesis, vesicular sequestration, and norepinephrine recycling via neuronal reuptake contribute importantly to the myocardial norepinephrine deficiency attending Lewy body diseases. The finding that a substantial proportion of catecholaminergic neurons are "sick but not dead" offers new hope for disease-modification strategies that might slow or prevent progression of this family of neurodegenerative disorders.

Funding: The research reported here was supported by the Division of Intramural Research, NINDS.

Declaration of Interest: The Authors have no conflicts of interest to disclose.

Ethical Approval: For all the subjects, written informed consent was obtained prior to participation in protocols approved by the Institutional Review Board of the National Institute of Neurological Disorders and Stroke, or else the next of kin gave written informed consent for post-mortem tissue harvesting for research purposes.

Suggested Citation

Goldstein, David S. and Pekker, Mark and Eisenhofer, Graeme and Sharabi, Yehonatan, 'Sick But Not Dead': Multiple Denervation-Independent Abnormalities of Myocardial Noradrenergic Function in Lewy Body Diseases (May 3, 2019). Available at SSRN: https://ssrn.com/abstract=3382404

David S. Goldstein (Contact Author)

Government of the United States of America - Autonomic Medicine Section (formerly Clinical Neurocardiology Section ( email )

Bethesda, MD
United States

Mark Pekker

University of Alabama at Huntsville

Huntsville, AL 35899
United States

Graeme Eisenhofer

Dresden University of Technology

Einsteinstrasse 3
Dresden, 01062
Germany

Yehonatan Sharabi

Tel Aviv University - Sackler Faculty of Medicine

Tel Aviv University
Ramat Aviv, 69978
Israel

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