Cardiac Sympathetic Hypo-innervation in Familial Dysautonomia

Overview

Journal Clin Auton Res

Date 2008 May 24

PMID 18498023

Citations 18

Authors

David S Goldstein

Basil Eldadah

Yehonatan Sharabi

Felicia B Axelrod

Affiliations

Soon will be listed here.

Abstract

Objective: Familial dysautonomia (FD) involves incomplete development of the sympathetic nervous system. Whether such loss extends to sympathetic innervation of the heart has been unknown. This study used 6-[(18)F]fluorodopamine neuroimaging to assess cardiac sympathetic innervation and function in FD.

Methods: Six adult FD patients underwent thoracic PET scanning for 30 minutes after i.v. 6-[(18)F]fluorodopamine injection, as did healthy volunteers without (N = 21) or with (N = 10) pre-treatment by desipramine, which interferes with neuronal uptake and thereby simulates effects of noradrenergic denervation. Effective rate constants for uptake and loss were calculated using a single compartment pharmacokinetic model.

Results: FD patients had decreased uptake and accelerated loss of 6-[(18)F]fluorodopamine-derived radioactivity in the interventricular myocardial septum (P = 0.009, P = 0.05) and ventricular free wall (P = 0.007, P < 0.001), compared to untreated controls. Desipramine-treated subjects had decreased uptake but normal loss of 6-[(18)F]fluorodopamine-derived radioactivity.

Conclusions: FD involves cardiac noradrenergic hypo-innervation. Since accelerated loss of 6-[(18)F]fluorodopamine-derived radioactivity cannot be explained by decreased neuronal uptake alone, FD may also involve augmented NE loss from extant terminals.

Citing Articles

Familial dysautonomia.

Gonzalez-Duarte A, Cotrina-Vidal M, Kaufmann H, Norcliffe-Kaufmann L Clin Auton Res. 2023; 33(3):269-280.

PMID: 37204536 DOI: 10.1007/s10286-023-00941-1.

Norepinephrine transporter defects lead to sympathetic hyperactivity in Familial Dysautonomia models.

Wu H, Yu W, Saito-Diaz K, Huang C, Carey J, Lefcort F Nat Commun. 2022; 13(1):7032.

PMID: 36396637 PMC: 9671909. DOI: 10.1038/s41467-022-34811-7.

Rescue of a familial dysautonomia mouse model by AAV9-Exon-specific U1 snRNA.

Romano G, Riccardi F, Bussani E, Vodret S, Licastro D, Ragone I Am J Hum Genet. 2022; 109(8):1534-1548.

PMID: 35905737 PMC: 9388384. DOI: 10.1016/j.ajhg.2022.07.004.

Recent advances in radiotracers targeting norepinephrine transporter: structural development and radiolabeling improvements.

Chen X, Kudo T, Lapa C, Buck A, Higuchi T J Neural Transm (Vienna). 2020; 127(6):851-873.

PMID: 32274584 PMC: 7223405. DOI: 10.1007/s00702-020-02180-4.

Myocardial ischaemia reperfusion injury and cardioprotection in the presence of sensory neuropathy: Therapeutic options.

Bencsik P, Gomori K, Szabados T, Santha P, Helyes Z, Jancso G Br J Pharmacol. 2020; 177(23):5336-5356.

PMID: 32059259 PMC: 7680004. DOI: 10.1111/bph.15021.

References

Taki J, Nakajima K, Hwang E, Matsunari I, Komai K, Yoshita M . Peripheral sympathetic dysfunction in patients with Parkinson's disease without autonomic failure is heart selective and disease specific. taki@med.kanazawa-u.ac.jp. Eur J Nucl Med. 2000; 27(5):566-73. DOI: 10.1007/s002590050544. View

Goldstein D, Katzper M, Linares O, Kopin I . Kinetic model for the fate of 6-[18F]fluorodopamine in the human heart: a novel means to examine cardiac sympathetic neuronal function. Naunyn Schmiedebergs Arch Pharmacol. 2002; 365(1):38-49. DOI: 10.1007/s002100100426. View

Freedman L, Ebstein R, Goldstein M, Axelrod F, DANCIS J . Serum dopamine-beta-hydroxylase in familial dysautonomia. J Lab Clin Med. 1975; 85(6):1008-12. View

Pearson J, Brandeis L, Goldstein M . Tyrosine hydroxylase immunoreactivity in familial dysautonomia. Science. 1979; 206(4414):71-2. DOI: 10.1126/science.39339. View

Gold-von Simson G, Rutkowski M, Berlin D, Axelrod F . Pacemakers in patients with familial dysautonomia--a review of experience with 20 patients. Clin Auton Res. 2005; 15(1):15-20. DOI: 10.1007/s10286-005-0218-2. View

Axelrod F . A world without pain or tears. Clin Auton Res. 2006; 16(2):90-7. DOI: 10.1007/s10286-006-0326-7. View

GOODALL M, GITLOW S, Alton H . Decreased noradrenaline (norepinephrine) synthesis in familial dysautonomia. J Clin Invest. 1971; 50(12):2734-40. PMC: 292223. DOI: 10.1172/JCI106774. View

Goldstein D, Holmes C, Stuhlmuller J, Lenders J, Kopin I . 6-[18F]fluorodopamine positron emission tomographic scanning in the assessment of cardiac sympathoneural function--studies in normal humans. Clin Auton Res. 1997; 7(1):17-29. DOI: 10.1007/BF02267622. View

Goldstein D, Holmes C, Li S, Bruce S, Metman L, Cannon 3rd R . Cardiac sympathetic denervation in Parkinson disease. Ann Intern Med. 2000; 133(5):338-47. DOI: 10.7326/0003-4819-133-5-200009050-00009. View

10.

Glickstein J, Axelrod F, Friedman D . Electrocardiographic repolarization abnormalities in familial dysautonomia: an indicator of cardiac autonomic dysfunction. Clin Auton Res. 1999; 9(2):109-12. DOI: 10.1007/BF02311768. View

11.

Slaugenhaupt S, Blumenfeld A, Gill S, Leyne M, Mull J, Cuajungco M . Tissue-specific expression of a splicing mutation in the IKBKAP gene causes familial dysautonomia. Am J Hum Genet. 2001; 68(3):598-605. PMC: 1274473. DOI: 10.1086/318810. View

12.

Pearson J, Pytel B . Quantitative studies of sympathetic ganglia and spinal cord intermedio-lateral gray columns in familial dysautonomia. J Neurol Sci. 1978; 39(1):47-59. DOI: 10.1016/0022-510x(78)90187-9. View

13.

Pearson J, Gallo G, Gluck M, Axelrod F . Renal disease in familial dysautonomia. Kidney Int. 1980; 17(1):102-12. DOI: 10.1038/ki.1980.12. View

14.

Axelrod F, Goldberg J, Ye X, Maayan C . Survival in familial dysautonomia: Impact of early intervention. J Pediatr. 2002; 141(4):518-23. DOI: 10.1067/mpd.2002.127088. View

15.

Ziegler M, Lake C, Kopin I . Deficient sympathetic nervous response in familial dysautonomia. N Engl J Med. 1976; 294(12):630-3. DOI: 10.1056/NEJM197603182941202. View

16.

Smith A, Taylor T, Wortis S . Abnormal catechol amine metabolism in familial dysautonomia. N Engl J Med. 1963; 268:705-7. DOI: 10.1056/NEJM196303282681304. View

17.

Slaugenhaupt S, Mull J, Leyne M, Cuajungco M, Gill S, Hims M . Rescue of a human mRNA splicing defect by the plant cytokinin kinetin. Hum Mol Genet. 2004; 13(4):429-36. DOI: 10.1093/hmg/ddh046. View

18.

Rotstein A, Charrow J, Deal B . Documented transient third-degree atrioventricular block and asystole in a child with familial dysautonomia. Pediatr Cardiol. 2007; 29(1):202-4. DOI: 10.1007/s00246-007-9057-3. View

19.

Close P, Hawkes N, Cornez I, Creppe C, Lambert C, Rogister B . Transcription impairment and cell migration defects in elongator-depleted cells: implication for familial dysautonomia. Mol Cell. 2006; 22(4):521-31. DOI: 10.1016/j.molcel.2006.04.017. View

20.

Goldstein D, Grossman E, Tamrat M, Chang P, Eisenhofer G, Bacher J . Positron emission imaging of cardiac sympathetic innervation and function using 18F-6-fluorodopamine: effects of chemical sympathectomy by 6-hydroxydopamine. J Hypertens. 1991; 9(5):417-23. DOI: 10.1097/00004872-199105000-00005. View