Skip to main content
SpringerLink
Log in

Enhanced NO Signaling in Patients with Takotsubo Cardiomyopathy: Short-Term Pain, Long-Term Gain?

  • ORIGINAL ARTICLE
  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Purpose

Little information is available concerning the mechanism(s) underlying Takotsubo cardiomyopathy (TTC), other than evidence of associated catecholamine secretion. Given the known effects of catecholamines on endothelial function, we tested the hypothesis that TTC might also be associated with impairment of nitric oxide (NO) signaling. We now report an evaluation of NO signaling in TTC patients (vs. aged-matched controls) in relation to (a) severity of the acute attack and (b) rate of recovery.

Methods

In 56 patients with TTC, we utilized (1) platelet responsiveness to NO and (2) plasma levels of asymmetric dimethylarginine (ADMA) as indices of integrity of the cyclic guanosine monophosphate (cGMP) pathway. Additionally, endothelial progenitor cell (EPC) counts, which are partially NO-dependent, were evaluated. These parameters were measured at the time of diagnosis and 3 months thereafter, and compared with an aging female cohort (n = 81).

Results

The data suggested that both NO generation and effect were accentuated in TTC patients: ADMA concentrations were lower (p = 0.003), and responsiveness to NO substantially greater (p = 0.0001) than in controls both acutely and after 3 months. Markers of severity of TTC attacks directly correlated with NO responsiveness, while extent of recovery at 3 months varied inversely with ADMA concentrations.

Conclusion

TTC is associated with intensification of NO signaling relative to that in normal age-matched females. Our data are consistent with this intensified signal’s potential contribution to the extent of initial myocardial injury, but conversely to accelerated recovery.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Bybee KA, Kara T, Prasad A, Lerman A, Barsness GW, Wright RS, et al. Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction. Ann Intern Med. 2004;141:858–65.

    Article  PubMed  Google Scholar 

  2. Gianni M, Dentali F, Grandi AM, Sumner G, Hiralal R, Lonn E. Apical ballooning syndrome or takotsubo cardiomyopathy: a systematic review. Eur Heart J. 2006;27:1523–9.

    Article  PubMed  Google Scholar 

  3. Pilliere R, Mansencal N, Digne F, Lacombe P, Joseph T, Dubourg O. Prevalence of Tako-Tsubo syndrome in a large urban agglomeration. Am J Cardiol. 2006;98:662–5.

    Article  PubMed  Google Scholar 

  4. Sharkey SW, Windenburg DC, Lesser JR, Maron MS, Hauser RG, Lesser JN, et al. Natural history and expansive clinical profile of stress (Tako-Tsubo) cardiomyopathy. J Am Coll Cardiol. 2010;55:333–41.

    Article  PubMed  Google Scholar 

  5. Akashi Y. Reversible ventricular dysfunction takotsubo (ampulla-shaped) cardiomyopathy. Intern Med. 2005;44:175–6.

    Article  PubMed  Google Scholar 

  6. Elesber AA, Prasad A, Lennon RJ, Wright RS, Lerman A, Rihal CS. Four-year recurrence rate and prognosis of the apical ballooning syndrome. J Am Coll Cardiol. 2007;50:448–52.

    Article  PubMed  Google Scholar 

  7. Akashi YJ, Nakazawa K, Sakakibara M, Miyake F, Koike H, Sasaka K. The clinical features of takotsubo cardiomyopathy. QJM. 2003;96:563–73.

    Article  PubMed  CAS  Google Scholar 

  8. Wittstein IS, Thiemann DR, Lima JA, Baughman KL, Schulman SP, Gerstenblith G, et al. Neurohumoral features of myocardial stunning due to sudden emotional stress. N Engl J Med. 2005;352:539–48.

    Article  PubMed  CAS  Google Scholar 

  9. Yoshioka T, Hashimoto A, Tsuchihashi K, Nagao K, Kyuma M, Ooiwa H, et al. Clinical implications of midventricular obstruction and intravenous propranolol use in transient left ventricular apical ballooning (Tako-Tsubo cardiomyopathy). Am Heart J. 2008;155:526 e1–7.

    Article  Google Scholar 

  10. Mallamaci F, Tripepi G, Maas R, Malatino L, Boger R, Zoccali C. Analysis of the relationship between norepinephrine and asymmetric dimethyl arginine levels among patients with end-stage renal disease. J Am Soc Nephrol. 2004;15:435–41.

    Article  PubMed  CAS  Google Scholar 

  11. Lee CW, Li D, Channon KM, Paterson DJ. L-arginine supplementation reduces cardiac noradrenergic neurotransmission in spontaneously hypertensive rats. J Mol Cell Cardiol. 2009;47:149–55.

    Article  PubMed  CAS  Google Scholar 

  12. Chan NY, Seyedi N, Takano K, Levi R. An unsuspected property of natriuretic peptides: promotion of calcium-dependent catecholamine release via protein kinase G-mediated phosphodiesterase type 3 inhibition. Circulation. 2012;125:298–307.

    Article  PubMed  CAS  Google Scholar 

  13. Zhu WZ, Zheng M, Koch WJ, Lefkowitz RJ, Kobilka BK, Xiao RP. Dual modulation of cell survival and cell death by beta(2)-adrenergic signaling in adult mouse cardiac myocytes. Proc Natl Acad Sci U S A. 2001;98:1607–12.

    Article  PubMed  CAS  Google Scholar 

  14. Paur H, Wright PT, Sikkel MB, Tranter MH, Mansfield C, O’Gara P, et al. High levels of circulating epinephrine trigger apical cardiodepression in a beta2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy. Circulation. 2012;126:697–706.

    Article  PubMed  CAS  Google Scholar 

  15. Grant JF, Chittleborough CR, Taylor AW, Dal Grande E, Wilson DH, Phillips PJ, et al. The North West Adelaide Health Study: detailed methods and baseline segmentation of a cohort for selected chronic diseases. Epidemiol Perspect Innov. 2006;3:4.

    Article  PubMed  Google Scholar 

  16. Chirkov YY, Holmes AS, Willoughby SR, Stewart S, Wuttke RD, Sage PR, et al. Stable angina and acute coronary syndromes are associated with nitric oxide resistance in platelets. J Am Coll Cardiol. 2001;37:1851–7.

    Article  PubMed  CAS  Google Scholar 

  17. Boger RH. Asymmetric dimethylarginine (ADMA) modulates endothelial function–therapeutic implications. Vasc Med. 2003;8:149–51.

    Article  PubMed  Google Scholar 

  18. Fleissner F, Thum T. Critical role of the nitric oxide/reactive oxygen species balance in endothelial progenitor dysfunction. Antioxid Redox Signal. 2011;15:933–48.

    Article  PubMed  CAS  Google Scholar 

  19. Chirkov YY, Holmes AS, Chirkova LP, Horowitz JD. Nitrate resistance in platelets from patients with stable angina pectoris. Circulation. 1999;100:129–34.

    Article  PubMed  CAS  Google Scholar 

  20. Heresztyn T, Worthley MI, Horowitz JD. Determination of l-arginine and NG, NG - and NG, NG’ -dimethyl-L-arginine in plasma by liquid chromatography as AccQ-Fluor fluorescent derivatives. J Chromatogr B Analyt Technol Biomed Life Sci. 2004;805:325–9.

    Article  PubMed  CAS  Google Scholar 

  21. Rajendran S, Willoughby SR, Chan WP, Liberts EA, Heresztyn T, Saha M, et al. Polycystic ovary syndrome is associated with severe platelet and endothelial dysfunction in both obese and lean subjects. Atherosclerosis. 2009;204:509–14.

    Article  PubMed  CAS  Google Scholar 

  22. Lagerstedt SA, O’Kane DJ, Singh RJ. Measurement of plasma free metanephrine and normetanephrine by liquid chromatography-tandem mass spectrometry for diagnosis of pheochromocytoma. Clin Chem. 2004;50:603–11.

    Article  PubMed  CAS  Google Scholar 

  23. Nguyen TH, Neil CJ, Sverdlov AL, Mahadavan G, Chirkov YY, Kucia AM, et al. N-terminal pro-brain natriuretic protein levels in takotsubo cardiomyopathy. Am J Cardiol. 2011;108:1316–21.

    Article  PubMed  CAS  Google Scholar 

  24. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr. 1989;2:358–67.

    PubMed  CAS  Google Scholar 

  25. Neil C, Nguyen TH, Kucia A et al. Slowly resolving global myocardial inflammation/oedema in Tako-Tsubo cardiomyopathy: evidence from T2-weighted cardiac MRI. Heart (British Cardiac Society) 2012;98:1278–84.

    Google Scholar 

  26. Nef HM, Mollmann H, Hilpert P, Troidl C, Voss S, Rolf A, et al. Activated cell survival cascade protects cardiomyocytes from cell death in Tako-Tsubo cardiomyopathy. Eur J Heart Fail. 2009;11:758–64.

    Article  PubMed  CAS  Google Scholar 

  27. Forbes SP, Druhan LJ, Guzman JE, Parinandi N, Zhang L, Green-Church KB, et al. Mechanism of 4-HNE mediated inhibition of hDDAH-1: implications in no regulation. Biochemistry. 2008;47:1819–26.

    Article  PubMed  CAS  Google Scholar 

  28. Pope AJ, Druhan L, Guzman JE, Forbes SP, Murugesan V, Lu D, et al. Role of DDAH-1 in lipid peroxidation product-mediated inhibition of endothelial NO generation. Am J Physiol Cell Physiol. 2007;293:C1679–86.

    Article  PubMed  CAS  Google Scholar 

  29. Fiedler L. The DDAH/ADMA pathway is a critical regulator of NO signalling in vascular homeostasis. Cell Adh Migr. 2008;2:149–50.

    Article  PubMed  Google Scholar 

  30. Stuhlinger MC, Tsao PS, Her JH, Kimoto M, Balint RF, Cooke JP. Homocysteine impairs the nitric oxide synthase pathway: role of asymmetric dimethylarginine. Circulation. 2001;104:2569–75.

    Article  PubMed  CAS  Google Scholar 

  31. Antoniades C, Shirodaria C, Leeson P, Antonopoulos A, Warrick N, Van-Assche T, et al. Association of plasma asymmetrical dimethylarginine (ADMA) with elevated vascular superoxide production and endothelial nitric oxide synthase uncoupling: implications for endothelial function in human atherosclerosis. Eur Heart J. 2009;30:1142–50.

    Article  PubMed  CAS  Google Scholar 

  32. Prasad A, Lerman A, Rihal CS. Apical ballooning syndrome (Tako-Tsubo or stress cardiomyopathy): a mimic of acute myocardial infarction. Am Heart J. 2008;155:408–17.

    Article  PubMed  Google Scholar 

  33. Anfossi G, Russo I, Massucco P, Mattiello L, Trovati M. Catecholamines, via beta-adrenoceptors, increase intracellular concentrations of 3′,5′-cyclic guanosine monophosphate (cGMP) through nitric oxide in human platelets. Thromb Haemost. 2002;87:539–40.

    PubMed  CAS  Google Scholar 

  34. Ozuyaman B, Godecke A, Kusters S, Kirchhoff E, Scharf RE, Schrader J. Endothelial nitric oxide synthase plays a minor role in inhibition of arterial thrombus formation. Thromb Haemost. 2005;93:1161–7.

    PubMed  Google Scholar 

  35. Chirkov YY, Horowitz JD. Impaired tissue responsiveness to organic nitrates and nitric oxide: a new therapeutic frontier? Pharmacol Ther. 2007;116:287–305.

    Article  PubMed  CAS  Google Scholar 

  36. Zhang F, Chen L, Liu C, Qiu P, Wang A, Li L, et al. Up-regulation of protein tyrosine nitration in methamphetamine-induced neurotoxicity through DDAH/ADMA/NOS pathway. Neurochem Int. 2013;62:1055–64.

    Article  PubMed  CAS  Google Scholar 

  37. Kume T, Kawamoto T, Okura H, Toyota E, Neishi Y, Watanabe N, et al. Local release of catecholamines from the hearts of patients with Tako-Tsubo-like left ventricular dysfunction. Circ J. 2008;72:106–8.

    Article  PubMed  CAS  Google Scholar 

  38. Penna C, Bassino E, Alloatti G. Platelet activating factor: the good and the bad in the ischemic/reperfused heart. Exp Biol Med (Maywood). 2011;236:390–401.

    Article  CAS  Google Scholar 

  39. Barletta G, Del Pace S, Boddi M, Del Bene R, Salvadori C, Bellandi B, et al. Abnormal coronary reserve and left ventricular wall motion during cold pressor test in patients with previous left ventricular ballooning syndrome. Eur Heart J. 2009;30:3007–14.

    Article  PubMed  Google Scholar 

  40. Martin EA, Prasad A, Rihal CS, Lerman LO, Lerman A. Endothelial function and vascular response to mental stress are impaired in patients with apical ballooning syndrome. J Am Coll Cardiol. 2010;56:1840–6.

    Article  PubMed  Google Scholar 

  41. Song BG, Park SJ, Noh HJ, Jo HC, Choi JO, Lee SC, et al. Clinical characteristics, and laboratory and echocardiographic findings in takotsubo cardiomyopathy presenting as cardiogenic shock. J Crit Care. 2010;25:329–35.

    Article  PubMed  CAS  Google Scholar 

  42. Boucher JL, Moali C, Tenu JP. Nitric oxide biosynthesis, nitric oxide synthase inhibitors and arginase competition for L-arginine utilization. Cell Mol Life Sci. 1999;55:1015–28.

    Article  PubMed  CAS  Google Scholar 

  43. Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet. 1992;339:572–5.

    Article  PubMed  CAS  Google Scholar 

  44. Chong CR, Law G, Neil CJ, Nguyen TH, Horowitz JD. Dissociation between severity of takotsubo cardiomyopathy and presentation with shock or hypotension. Clin Cardiol. 2013;36:401–6.

    Google Scholar 

  45. Lee DI, Vahebi S, Tocchetti CG, Barouch LA, Solaro RJ, Takimoto E, et al. PDE5A suppression of acute beta-adrenergic activation requires modulation of myocyte beta-3 signaling coupled to PKG-mediated troponin I phosphorylation. Basic Res Cardiol. 2010;105:337–47.

    Article  PubMed  CAS  Google Scholar 

  46. Li D, Qu Y, Tao L, Liu H, Hu A, Gao F, et al. Inhibition of iNOS protects the aging heart against beta-adrenergic receptor stimulation-induced cardiac dysfunction and myocardial ischemic injury. J Surg Res. 2006;131:64–72.

    Article  PubMed  CAS  Google Scholar 

  47. Valbusa A, Abbadessa F, Giachero C, Vischi M, Zingarelli A, Olivieri R, et al. Long-term follow-up of Tako-Tsubo-like syndrome: a retrospective study of 22 cases. J Cardiovasc Med (Hagerstown). 2008;9:805–9.

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. The Queen Elizabeth Hospital, Department of Cardiology, The University of Adelaide, Adelaide, Australia

    Thanh H. Nguyen, Christopher J. Neil, Aaron L. Sverdlov, Doan T. Ngo, Wai P. Chan, Tamila Heresztyn, Yuliy Y. Chirkov & John D. Horowitz

  2. Institute of Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625, Hannover, Germany

    Dimitrios Tsikas

  3. The University of Aberdeen, Aberdeen, UK

    Michael P. Frenneaux

  4. Cardiology Unit, The Queen Elizabeth Hospital, 28 Woodville Road, Woodville South, SA, 5011, Australia

    John D. Horowitz

Authors
  1. Thanh H. Nguyen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Christopher J. Neil
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Aaron L. Sverdlov
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Doan T. Ngo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wai P. Chan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tamila Heresztyn
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yuliy Y. Chirkov
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Dimitrios Tsikas
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Michael P. Frenneaux
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. John D. Horowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to John D. Horowitz.

Additional information

J D Horowitz and YY Chirkov are co-inventors of a patent application entitled “Method for preventing and/or treating a stress induced cardiomyopathy” filed by the University of Adelaide.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nguyen, T.H., Neil, C.J., Sverdlov, A.L. et al. Enhanced NO Signaling in Patients with Takotsubo Cardiomyopathy: Short-Term Pain, Long-Term Gain?. Cardiovasc Drugs Ther 27, 541–547 (2013). https://doi.org/10.1007/s10557-013-6481-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-013-6481-x

Keywords

Search

Navigation