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Relationship of left ventricular global longitudinal strain with cardiac autonomic denervation as assessed by 123I-mIBG scintigraphy in patients with heart failure with reduced ejection fraction submitted to cardiac resynchronization therapy

Assessment of cardiac autonomic denervation by GLS in patients with heart failure with reduced ejection fraction submitted to CRT

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Journal of Nuclear Cardiology Aims and scope



Heart failure (HF) is associated with cardiac autonomic denervation (AD), which can be non-invasively assessed by 123I-metaiodobenzylguanidine (123I-mIBG) scintigraphy and has prognostic implications. We aimed to study the relationship between myocardial contractility assessed by global longitudinal strain (GLS) and AD assessed by 123I-mIBG scintigraphy in advanced HF.


BETTER-HF is a prospective randomized clinical trial including HF patients (pts) submitted to cardiac resynchronization therapy (CRT) who are submitted to a clinical, echocardiographic, and scintigraphic assessment before and 6 months after CRT. 81 pts were included. An echocardiographic response (absolute increase in left ventricular ejection fraction ≥ 10%) was observed in 73.7% of pts. A higher baseline late heart-to-mediastinum ratio (HMR) was associated with a better echocardiographic response. There was a significant association between late HMR and GLS at baseline and 6 months. At baseline, GLS had an AUC of 0.715 for discrimination for a late HMR < 1.6. A GLS cut-off of − 9% maximized the likelihood of correctly classifying a pt as having severe AD (HMR < 1.6).


Myocardial contractility as assessed by GLS is moderately correlated with AD as assessed by 123I-mIBG scintigraphy and has a good discrimination for the identification of severe cardiac denervation. GLS may allow for a more readily accessible estimation of the degree of AD in advanced HF pts.

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Cardiac resynchronization therapy


Global longitudinal strain


Heart-to-mediastinum ratio


Heart failure with reduced ejection fraction


Intraclass correlation coefficient


Left ventricular ejection fraction


Washout rate


  1. Roger V. Epidemiology of heart failure. Circ Res 2013;113:646-59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Mosterd A, Hoes AW. Clinical epidemiology of heart failure. Heart 2007;93:1137-46.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Crespo-Leiro MG, Anker SD, Maggioni AP, Coats AJ, Filippatos G, Ruschitzka F, et al. European Society of Cardiology Heart Failure Long-Term Registry (ESC-HF-LT): 1-Year follow-up outcomes and differences across regions. Eur J Heart Fail 2016;18:613-25.

    Article  PubMed  Google Scholar 

  4. Packer M. The neurohormonal hypothesis: A theory to explain the mechanism of disease progression in heart failure. J Am Coll Cardiol 1992;20:248-54.

    Article  CAS  PubMed  Google Scholar 

  5. Bristow MR, Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie K, et al. Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N Engl J Med 1982;307:205-11.

    Article  CAS  PubMed  Google Scholar 

  6. Kaye DM, Lefkovits J, Jennings GL, Bergin P, Broughton A, Esler MD. Adverse consequences of high sympathetic nervous activity in the failing human heart. J Am Coll Cardiol 1995;26:1257-63.

    Article  CAS  PubMed  Google Scholar 

  7. Patel AD, Iskandrian AE. mIBG imaging. J Nucl Cardiol 2002;9:75-94.

    Article  PubMed  Google Scholar 

  8. 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.

    Article  PubMed  Google Scholar 

  9. 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.

    Article  PubMed  Google Scholar 

  10. 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.

    Article  PubMed  Google Scholar 

  11. Nakata T, Nakajima K, Yamashina S, Yamada T, Momose M, Kasama S, et al. A pooled analysis of multicenter cohort studies of 123I-mIBG imaging of sympathetic innervation for assessment of long-term prognosis in heart failure. J Am Coll Cardiol Imaging 2013;6:772-84.

    Article  Google Scholar 

  12. Arora R, Ferrick KJ, Nakata T, Kaplan RC, Rozengarten M, Latif F, et al. I-123 mIBG imaging and heart rate variability analysis to predict the need for an implantable cardioverter defibrillator. J Nucl Cardiol 2003;10:121-31.

    Article  PubMed  Google Scholar 

  13. Boogers MJ, Borleffs CJ, Henneman MM, van Bommel RJ, van Ramshorst J, Boersma E, et al. Cardiac sympathetic denervation assessed with 123-iodine metaiodobenzylguanidine imaging predicts ventricular arrhythmias in implantable cardioverter-defibrillator patients. J Am Coll Cardiol 2010;55:2769-77.

    Article  PubMed  Google Scholar 

  14. Tamaki S, Yamada T, Okuyama Y, Morita T, Sanada S, Tsukamoto Y, et al. Cardiac iodine-123 metaiodobenzylguanidine imaging predicts sudden cardiac death independently of left ventricular ejection fraction in patients with chronic heart failure and left ventricular systolic dysfunction: Results from a comparative study with signal-averaged electrocardiogram, heart rate variability, and QT dispersion. J Am Coll Cardiol 2009;53:426-35.

    Article  CAS  PubMed  Google Scholar 

  15. Kasama S, Toyama T, Hatori T, Sumino H, Kumakura H, Takayama Y, et al. Evaluation of cardiac sympathetic nerve activity and left ventricular remodelling in patients with dilated cardiomyopathy on the treatment containing carvedilol. Eur Heart J 2007;28:989-95.

    Article  CAS  PubMed  Google Scholar 

  16. Takeishi Y, Atsumi H, Fujiwara S, Takahashi K, Tomoike H. ACE inhibition reduces cardiac iodine-123-mIBG release in heart failure. J Nucl Med 1997;38:1085-9.

    CAS  PubMed  Google Scholar 

  17. Kasama S, Toyama T, Kumakura H, Takayama Y, Ichikawa S, Suzuki T, et al. Spironolactone improves cardiac sympathetic nerve activity and symptoms in patients with congestive heart failure. J Nucl Med 2002;43:1279-85.

    CAS  PubMed  Google Scholar 

  18. Kasama S, Toyama T, Sumino H, Nakazawa M, Matsumoto N, Sato Y, et al. Prognostic value of serial cardiac 123I-mIBG imaging in patients with stabilized chronic heart failure and reduced left ventricular ejection fraction. J Nucl Med 2008;49:907-14.

    Article  PubMed  Google Scholar 

  19. Nishioka SA, Martinelli Filho M, Brandão SC, Giorgi MC, Vieira ML, Costa R, et al. Cardiac sympathetic activity pre and post resynchronization therapy evaluated by 123I-mIBG myocardial scintigraphy. J Nucl Cardiol 2007;14:852-9.

    Article  PubMed  Google Scholar 

  20. Burri H, Sunthorn H, Somsen A, Fleury E, Stettler C, Shah D, et al. Improvement in cardiac sympathetic nerve activity in responders to resynchronization therapy. Europace 2008;10:374-8.

    Article  PubMed  Google Scholar 

  21. Cha YM, Oh J, Miyazaki C, Hayes DL, Rea RF, Shen WK, et al. Cardiac resynchronization therapy upregulates cardiac autonomic control. J Cardiovasc Electrophysiol 2008;19:1045-52.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Shinohara T, Takahashi N, Saito S, Okada N, Wakisaka O, Yufu K, et al. Effect of cardiac resynchronization therapy on cardiac sympathetic nervous dysfunction and serum C-reactive protein level. Pacing Clin Electrophysiol 2011;34:1225-30.

    Article  PubMed  Google Scholar 

  23. Tanaka H, Tatsumi K, Fujiwara S, Tsuji T, Kaneko A, Ryo K, et al. Effect of left ventricular dyssynchrony on cardiac sympathetic activity in heart failure patients with wide QRS duration. Circ J 2012;76:382-9.

    Article  PubMed  Google Scholar 

  24. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2015;28:1-39.e14.

    Article  Google Scholar 

  25. Bertini M, Ng AC, Antoni ML, Nucifora G, Ewe SH, Auger D, et al. Global longitudinal strain predicts long-term survival in patients with chronic ischemic cardiomyopathy. Circ Cardiovasc Imaging 2012;5:383-91.

    Article  PubMed  Google Scholar 

  26. Sengelov M, Jorgensen PG, Jensen JS, Bruun NE, Olsen FJ, Fritz-Hansen T, et al. Global longitudinal strain is a superior predictor of all-cause mortality in heart failure with reduced ejection fraction. JACC Cardiovasc Imaging 2015;8:1351-9.

    Article  PubMed  Google Scholar 

  27. Nagueh SF, Smiseth OA, Appleton CP, Byrd BF, Dokainish H, Edvardsen T, et al. Recommendations for the evaluation of left ventricular diastolic function by echocardiography: An update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr 2016;29:277-314.

    Article  PubMed  Google Scholar 

  28. Stanton T, Leano R, Marwick TH. Prediction of all-cause mortality from global longitudinal speckle strain comparison with ejection fraction and wall motion scoring. Circ Cardiovasc Imaging 2009;2:356-64.

    Article  PubMed  Google Scholar 

  29. Rickard J, Baranowski B, Wilson Tang WH, Grimm RA, Niebauer M, Cantillion D, et al. Echocardiographic predictors of long-term survival in patients undergoing cardiac resynchronization therapy: What is the optimal metric? J Cardiovasc Electrophysiol 2017;28:410-5.

    Article  PubMed  Google Scholar 

  30. Veltman CE, Boogers MJ, Meinardi JE, Younis IA, Dibbets-Schneider P, Van der Wall EE, et al. Reproducibility of planar 123I-meta-iodobenzylguanidine (mIBG) myocardial scintigraphy in patients with heart failure. Eur J Nucl Med Mol Imaging 2012;39:1599-608.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Leimbach WN, Wallin BG, Victor RG, Aylward PE, Sundlöf G, Mark AL. Direct evidence from intraneural recordings for increased central sympathetic outflow in patients with heart failure. Circulation 1986;73:913-9.

    Article  PubMed  Google Scholar 

  32. Agostini D, Verberne HJ, Hamon M, Jacobson AF, Manrique A. Cardiac 123I-mIBG scintigraphy in heart failure. Q J Nucl Med Mol Imaging 2008;52:369-77.

    CAS  PubMed  Google Scholar 

  33. Shibata M, Morita Y, Shimizu T, Takahashi K, Suzuki N. Cardiac parasympathetic dysfunction concurrent with cardiac sympathetic denervation in Parkinson’s disease. J Neurol Sci 2009;276:79-83.

    Article  PubMed  Google Scholar 

  34. Spiegel J, Hellwig D, Farmakis G, Jost WH, Samnick S, Fassbender K, et al. Myocardial sympathetic degeneration correlates with clinical phenotype of Parkinson’s disease. Mov Disord 2007;22:1004-8.

    Article  PubMed  Google Scholar 

  35. Rosner B. The intraclass correlation coefficient. In: Fundamentals of biostatistics. 6th ed. Belmont: Duxbury, Thomson Brooks/Cole; 2006. p. 613-5.

  36. Nishisato K, Hashimoto A, Nakata T, Doi T, Yamamoto H, Nagahara D, et al. Impaired cardiac sympathetic innervation and myocardial perfusion are related to lethal arrhythmia: Quantification of cardiac tracers in patients with ICDs. J Nucl Med 2010;51:1241-9.

    Article  PubMed  Google Scholar 

  37. Nagahara D, Nakata T, Hashimoto A, Wakabayashi T, Kyuma M, Noda R, et al. Predicting the need for an implantable cardioverter defibrillator using cardiac metaiodobenzylguanidine activity together with plasma natriuretic peptide concentration or left ventricular function. J Nucl Med 2008;49:225-33.

    Article  PubMed  Google Scholar 

  38. Al Badarin FJ, Wimmer AP, Kennedy KF, Jacobson AF, Bateman TM. The utility of ADMIRE-HF risk score in predicting serious arrhythmic events in heart failure patients: Incremental prognostic benefit of cardiac 123I-mIBG scintigraphy. J Nucl Cardiol 2014;21:756-62.

    Article  PubMed  Google Scholar 

  39. Rickard J, Michtalik H, Sharma R, Berger Z, Iyoha E, Green AR, et al. Predictors of response to cardiac resynchronization therapy: A systematic review. Int J Cardiol 2016;225:345-52.

    Article  PubMed  Google Scholar 

  40. Chatterjee NA, Singh JP. Cardiac resynchronization therapy: Past, present, and future. Heart Fail Clin 2015;11:287-303.

    Article  PubMed  Google Scholar 

  41. Leitman M, Lysyansky P, Sidenko S, Shir V, Peleg E, Binenbaum M, et al. Two-dimensional strain—A novel software for real-time quantitative echocardiographic assessment of myocardial function. J Am Soc Echocardiogr 2004;17:1021-9.

    Article  PubMed  Google Scholar 

  42. Cho GY, Chan J, Leano R, Strudwick M, Marwick TH. Comparison of two-dimensional speckle and tissue velocity based strain and validation with harmonic phase magnetic resonance imaging. Am J Cardiol 2006;97:1661-6.

    Article  PubMed  Google Scholar 

  43. Ersbøll M, Valeur N, Mogensen UM, Andersen MJ, Møller JE, Velazquez EJ, et al. Prediction of all-cause mortality and heart failure admissions from global left ventricular longitudinal strain in patients with acute myocardial infarction and preserved left ventricular ejection fraction. J Am Coll Cardiol 2013;61:2365-73.

    Article  PubMed  Google Scholar 

  44. Mignot A, Donal E, Zaroui A, Reant P, Salem A, Hamon C, et al. Global longitudinal strain as a major predictor of cardiac events in patients with depressed left ventricular function: A multicenter study. J Am Soc Echocardiogr 2010;23:1019-24.

    Article  PubMed  Google Scholar 

  45. Bulten BF, Verberne HJ, Bellersen L, Oyen WJ, Sabaté-Llobera A, Mavinkurve-Groothuis AM, et al. Relationship of promising methods in the detection of anthracycline-induced cardiotoxicity in breast cancer patients. Cancer Chemother Pharmacol 2015;76:957-67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cohen J. The significance of a product moment rs. In: Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale: Lawrence Erlbaum Associates; 1988. p. 75-107.

  47. Chen W, Cao Q, Dilsizian V. Variation of heart-to-mediastinal ratio in (123)I-mIBG cardiac sympathetic imaging: Its affecting factors and potential corrections. Curr Cardiol Rep 2011;13:132-7.

    Article  PubMed  Google Scholar 

  48. Nakajima K, Okuda K, Yoshimura M, Matsuo S, Wakabayashi H, Imanishi Y, et al. Multicenter cross-calibration of I-123 metaiodobenzylguanidine heart-to-mediastinum ratios to overcome camera-collimator variations. J Nucl Cardiol 2014;21:970-8.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Verberne HJ, Habraken JB, van Eck-Smit BL, Agostini D, Jacobson AF. Variations in 123I-metaiodobenzylguanidine (mIBG) late heart mediastinal ratios in chronic heart failure: A need for standardisation and validation. Eur J Nucl Med Mol Imaging 2008;35:547-53.

    Article  CAS  PubMed  Google Scholar 

  50. Tsuchimochi S, Tamaki N, Tadamura E, Kawamoto M, Fujita T, Yonekura Y, et al. Age and gender differences in normal myocardial adrenergic neuronal function evaluated by iodine-123-mIBG imaging. J Nucl Med 1995;36:969-74.

    CAS  PubMed  Google Scholar 

  51. Sakata K, Shirotani M, Yoshida H, Kurata C. Physiological fluctuation of the human left ventricle sympathetic nervous system assessed by iodine-123-mIBG. J Nucl Med 1998;39:1667-71.

    CAS  PubMed  Google Scholar 

  52. Wakabayashi T, Nakata T, Hashimoto A, Yuda S, Tsuchihashi K, Travin MI, et al. Assessment of underlying etiology and cardiac sympathetic innervation to identify patients at high risk of cardiac death. J Nucl Med 2001;42:1757-67.

    CAS  PubMed  Google Scholar 

  53. Stefanelli A, Treglia G, Giordano A. (123)I-mIBG scintigraphy as a powerful tool to plan an implantable cardioverter defibrillator and to assess cardiac resynchronization therapy in heart failure patients. Int J Mol Imaging 2012;2012:690468.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Correspondence to Madalena Coutinho Cruz MD.

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Madalena C. Cruz, Ana Abreu, Guilherme Portugal, Helena Santa-Clara, Pedro S. Cunha, Mario M. Oliveira, Vanessa Santos, Luís Oliveira, Pedro Rio, Inês Rodrigues, Luís A. Morais, Rui C. Ferreira, and Miguel. M. Carmo have no conflicts of interest to declare.

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Cruz, M.C., Abreu, A., Portugal, G. et al. Relationship of left ventricular global longitudinal strain with cardiac autonomic denervation as assessed by 123I-mIBG scintigraphy in patients with heart failure with reduced ejection fraction submitted to cardiac resynchronization therapy. J. Nucl. Cardiol. 26, 869–879 (2019).

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