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Open Access 01-06-2018 | Original Article

Polymorphism of SLC6A2 gene does not influence outcome of myocardial ¹²³I-mIBG scintigraphy in patients with chronic heart failure

Authors: Derk O. Verschure, MD, F. Baas, MD, PhD, Berthe L. F. van Eck-Smit, MD, PhD, G. Aernout Somsen, MD, PhD, Hein J. Verberne, MD, PhD

Published in: Journal of Nuclear Cardiology | Issue 3/2018

Abstract

Aim

The NET, encoded by SLC6A2, is responsible for presynaptic NE-reuptake. ¹²³I-mIBG is clinically used to evaluate cardiac sympathetic function. However, it is unknown if polymorphism of SLC6A2 influences cardiac sympathetic activity as assessed with ¹²³I-mIBG. Therefore we studied the influence of SLC6A2 SNPs on myocardial ¹²³I-mIBG parameters in CHF.

Materials and Methods

Forty-nine adults with stable CHF (age 66.5 ± 8.1 years, LVEF 22.3 ± 6.4) were enrolled. Fifteen minutes (early) and 4 hours (late) after administration of ¹²³I-mIBG planar images were acquired. The H/M ratio was calculated from the manually drawn ROI over the left ventricle and a fixed mediastinal ROI. Fourteen exons of the SLC6A2 gene were analyzed from whole blood samples.

Results

We found 6 different SLC6A2 SNPs, although none were functional. LVEF was the only independent predictor for early (adjusted R ² = 0.063, p = 0.045) and late H/M ratio (adjusted R ² = 0.116, p = 0.010). NT-proBNP was the only independent predictor for ¹²³I-mIBG WO (adjusted R ² = 0.074, p = 0.032). SLC6A2 SNPs were not associated with any myocardial ¹²³I-mIBG-derived parameter.

Conclusion

In this specific CHF population polymorphism of SLC6A2 gene was not associated with any ¹²³I-mIBG derived parameters.

Pierpont GL, DeMaster EG, Reynolds S, Pederson J, Cohn JN. Ventricular myocardial catecholamines in primates. J lab Clin Med. 1985;106:205-10.PubMed

Esler M, Jennings G, Lambert G, Meredith I, Horne M, Eisenhofer G. Overflow of catecholamine neurotransmitters to the circulation: source, fate, and functions. Physiol Rev. 1990;70:963-85.CrossRefPubMed

Chen NH, Reith ME, Quick MW. Synaptic uptake and beyond: the sodium- and chloride-dependent neurotransmitter transporter family SLC6. Pflugers Arch. 2004;447:519-31.CrossRefPubMed

Bruss M, Kunz J, Lingen B, Bönisch H. Chromosomal mapping of the human gene for the tricyclic antidepressant-sensitive noradrenaline transporter. Hum Genet. 1993;91:278-80.CrossRefPubMed

Hahn MK, Blakely RD. Monoamine transporter gene structure and polymorphisms in relation to psychiatric and other complex disorders. Pharmacogenomics J. 2002;2:217-35.CrossRefPubMed

Stober G, Nothen MM, Porzgen P, Brüss M, Bönisch H, Knapp M, et al. Systematic search for variation in the human norepinephrine transporter gene: identification of five naturally occurring missense mutations and study of association with major psychiatric disorders. Am J Med Genet. 1996;67:523-32.CrossRefPubMed

Runkel F, Bruss M, Nothen MM, Stöber G, Propping P, Bönisch H. Pharmacological properties of naturally occurring variants of the human norepinephrine transporter. Pharmacogenetics. 2000;10:397-405.CrossRefPubMed

Iwasa H, Kurabayashi M, Nagai R, Nakamura Y, Tanaka T. Genetic variations in five genes involved in the excitement of cardiomyocytes. J Hum Genet. 2001;46:549-52.CrossRefPubMed

Halushka MK, Fan JB, Bentley K, Hsie L, Shen N, Weder A, et al. Patterns of single-nucleotide polymorphisms in candidate genes for blood-pressure homeostasis. Nat Genet. 1999;22:239-47.CrossRefPubMed

10.

Shannon JR, Flattem NL, Jordan J, Jacob G, Black BK, Biaggioni I, et al. Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N Engl J Med. 2000;342:541-9.CrossRefPubMed

11.

Hahn MK, Robertson D, Blakely RD. A mutation in the human norepinephrine transporter gene (SLC6A2) associated with orthostatic intolerance disrupts surface expression of mutant and wild-type transporters. J Neurosci. 2003;23:4470-8.CrossRefPubMed

12.

Hasking GJ, Esler MD, Jennings GL, Burton D, Johns JA, Korner PI. Norepinephrine spillover to plasma in patients with congestive heart failure: evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation. 1986;73:615-21.CrossRefPubMed

13.

Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med. 1984;311:819-23.CrossRefPubMed

14.

Rundqvist B, Elam M, Bergmann-Sverrisdottir Y, Eisenhofer G, Friberg P. Increased cardiac adrenergic drive precedes generalized sympathetic activation in human heart failure. Circulation. 1997;95:169-75.CrossRefPubMed

15.

Merlet P, Delforge J, Syrota A, Angevin E, Mazière B, Crouzel C, et al. Positron emission tomography with 11C CGP-12177 to assess beta-adrenergic receptor concentration in idiopathic dilated cardiomyopathy. Circulation. 1993;87:1169-78.CrossRefPubMed

16.

Wieland DM, Brown LE, Les Rogers W, Worthington KC, Wu JL, Clinthorne NH, et al. Myocardial Imaging with a Radioiodinated Norepinephrine Storage Analog. J Nucl Med. 1981;22:22-31.PubMed

17.

Schofer J, Spielmann R, Schuchert A, Weber K, Schlüter M. Iodine-123 meta-iodobenzylguanidine scintigraphy: a noninvasive method to demonstrate myocardial adrenergic nervous system disintegrity in patients with idiopathic dilated cardiomyopathy. J Am Coll Cardiol. 1988;12:1252-8.CrossRefPubMed

18.

Wichter T, Hindricks G, Lerch H, Bartenstein P, Borggrefe M, Schober O, et al. Regional myocardial sympathetic dysinnervation in arrhythmogenic right ventricular cardiomyopathy. An analysis using 123I-meta-iodobenzylguanidine scintigraphy. Circulation. 1994;89:667-83.CrossRefPubMed

19.

Shimizu M, Ino H, Yamaguchi M, Terai H, Hayashi K, Nakajima K, et al. Heterogeneity of cardiac sympathetic nerve activity and systolic dysfunction in patients with hypertrophic cardiomyopathy. J Nucl Med. 2002;43:15-20.PubMed

20.

Jacobson AF, Senior R, Cerqueira MD, Wong ND, Thomas GS, Lopez VA, et al. Myocardial iodine-123 meta-iodobenzylguanidine imaging and cardiac events in heart failure. Results of the prospective ADMIRE-HF (AdreView Myocardial Imaging for Risk Evaluation in Heart Failure) study. J Am Coll Cardiol. 2010;55:2212-21.CrossRefPubMed

21.

Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology. Eur Heart J. 2016;37:2129-200.CrossRefPubMed

22.

Flotats A, Carrió I, Agostini D, Le Guludec D, Marcassa C, Schäfers M, et al. Proposal for standardization of 123I-metaiodobenzylguanidine (MIBG) cardiac sympathetic imaging by the EANM Cardiovascular Committee and the European Council of Nuclear Cardiology. Eur J Nucl Med Mol Imaging. 2010;37:1802-12.CrossRefPubMed

23.

Nakajima K, Matsumoto N, Kasai T, Matsuo S, Kiso K, Okuda K. Normal values and standardization of parameters in nuclear cardiology: Japanese Society of Nuclear Medicine working group database. Ann Nucl Med. 2016;30:188-99.CrossRefPubMedPubMedCentral

24.

Verberne HJ, Brewster LM, Somsen GA, van Eck-Smit BL. Prognostic value of myocardial 123I-metaiodobenzylguanidine (MIBG) parameters in patients with heart failure: a systematic review. Eur Heart J. 2008;29:1147-59.CrossRefPubMed

25.

Green EA, Raj V, Shibao CA, Biaggioni I, Black BK, Dupont WD, et al. Effects of norepinephrine reuptake inhibition on postural tachycardia syndrome. J Am Heart Assoc. 2013;2:e000395.CrossRefPubMedPubMedCentral

26.

Kimura S, Miura Y, Adachi M, Adachi M, Nezu M, Toriyabe S, et al. The effect of sodium depletion on plasma norepinephrine kinetics in patients with essential hypertension. Circ J. 1983;47:1232-41.CrossRef

27.

Esler M, Jackman G, Bobik A, Leonard P, Kelleher D, Skews H, et al. Norepinephrine kinetics in essential hypertension. Defective neuronal uptake of norepinephrine in some patients. Hypertension. 1981;3:149-56.CrossRefPubMed

28.

Rumantir MS, Kaye DM, Jennings GL, Vaz M, Hastings JA, Esler MD. Phenotypic evidence of faulty neuronal norepinephrine reuptake in essential hypertension. Hypertension. 2000;36:824-9.CrossRefPubMed

29.

Hahn MK, Mazei-Robison MS, Blakely RD. Single nucleotide polymorphisms in the human norepinephrine transporter gene affect expression, trafficking, antidepressant interaction, and protein kinase C regulation. Mol Pharmacol. 2005;68:457-66.CrossRefPubMed

30.

Ono K, Iwanaga Y, Mannami T, Kokubo Y, Tomoike H, Komamura K, et al. Epidemiological evidence of an association between SLC6A2 gene polymorphism and hypertension. Hypertens Res. 2003;26:685-9.CrossRefPubMed

31.

Kopin IJ, Rundqvist B, Friberg P, Lenders J, Goldstein DS, Eisenhofer G. Different relationships of spillover to release of norepinephrine in human heart, kidneys, and forearm. Am J Physiol. 1998;275:R165-73.PubMed

32.

Tsutamoto T, Wada A, Maeda K, Mabuchi N, Hayashi M, Tsutsui T, et al. Angiotensin II type 1 receptor antagonist decreases plasma levels of tumor necrosis factor alpha, interleukin-6 and soluble adhesion molecules in patients with chronic heart failure. J Am Coll Cardiol. 2000;35:714-21.CrossRefPubMed

33.

Clarke L, Fairley S, Zheng-Bradley X, Streeter I, Perry E, Lowy E, et al. The international Genome sample resource (IGSR): A worldwide collection of genome variation incorporating the 1000 Genomes Project data. Nucleic Acids Res. 2016 [Epub ahead of print].

Title: Polymorphism of SLC6A2 gene does not influence outcome of myocardial 123I-mIBG scintigraphy in patients with chronic heart failure
Authors: Derk O. Verschure, MD
F. Baas, MD, PhD
Berthe L. F. van Eck-Smit, MD, PhD
G. Aernout Somsen, MD, PhD
Hein J. Verberne, MD, PhD
Publication date: 01-06-2018
Publisher: Springer US
Published in: Journal of Nuclear Cardiology / Issue 3/2018
Print ISSN: 1071-3581
Electronic ISSN: 1532-6551
DOI: https://doi.org/10.1007/s12350-016-0722-x

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Polymorphism of SLC6A2 gene does not influence outcome of myocardial ¹²³I-mIBG scintigraphy in patients with chronic heart failure

Abstract

Aim

Materials and Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Aim

Materials and Methods

Results

Conclusion

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