SpringerLink
Log in

Heart rate reserve is a long-term risk predictor in women undergoing myocardial perfusion imaging

  • Original Article
  • Published:
European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Background

Although women with cardiovascular disease experience relatively worse outcomes as compared to men, substantial knowledge gaps remain regarding the unique female determinants of cardiovascular risk. Heart rate (HR) responses to vasodilator stress mirror autonomic activity and may carry important long-term prognostic information in women.

Methods and results

Hemodynamic changes during adenosine stress were recorded in a total of 508 consecutive patients (104 women) undergoing clinically indicated 13N-ammonia Positron-Emission-Tomography (PET) at our institution. Following propensity matching, 202 patients (101 women, mean age 61.3 ± 12.6 years) were analyzed. During a median follow-up of 5.6 years, 97 patients had at least one cardiac event, including 17 cardiac deaths. Heart rate reserve (% HRR) during adenosine infusion was significantly higher in women as compared to men (23.8 ± 19.5 vs 17.3 ± 15.3, p = 0.009). A strong association between 10-year cardiovascular endpoints and a blunted HRR was observed in women, while this association was less pronounced in men. Accordingly, in women, but not in men, reduced HRR was selected as a strong predictor for adverse cardiovascular events in a Cox regression model fully adjusted for imaging findings and traditional risk factors (HR 2.41, 95% CI 1.23–4.75, p = 0.011). Receiver operating characteristics (ROC) curves revealed that a blunted HRR <21% was a powerful predictor for MACE in women with a sensitivity of 77% and a specificity of 68%.

Conclusion

Blunted HRR to adenosine stress adds incremental prognostic value for long-term cardiovascular outcomes in women beyond that provided by traditional risk factors and imaging findings.

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

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

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

Abbreviations

BMI:

Body mass index

CAD:

Coronary artery disease

CFR:

Coronary flow reserve

CT:

Computed tomography

HRR:

Heart rate reserve

LVEF:

Left ventricular ejection fraction

MAP:

Mean arterial pressure

CMVD:

coronary microvascular dysfunction

References

  1. Timmis A, Townsend N, Gale C, Grobbee R, Maniadakis N, Flather M, et al. European Society of Cardiology: cardiovascular disease statistics 2017. Eur Heart J. 2018;39(7):508–79.

    Article  PubMed  Google Scholar 

  2. Wilmot KA, O’Flaherty M, Capewell S, Ford ES, Vaccarino V. Coronary heart disease mortality declines in the United States from 1979 through 2011: evidence for stagnation in young adults, especially women. Circulation. 2015;132(11):997–1002.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Murthy VL, Naya M, Taqueti VR, Foster CR, Gaber M, Hainer J, et al. Effects of sex on coronary microvascular dysfunction and cardiac outcomes. Circulation. 2014;129(24):2518–27.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Pepine CJ, Ferdinand KC, Shaw LJ, Light-McGroary KA, Shah RU, Gulati M, et al. Emergence of nonobstructive coronary artery disease: a woman’s problem and need for change in definition on angiography. J Am Coll Cardiol. 2015;66(17):1918–33.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Reis SE, Holubkov R, Conrad Smith AJ, Kelsey SF, Sharaf BL, Reichek N, et al. Coronary microvascular dysfunction is highly prevalent in women with chest pain in the absence of coronary artery disease: results from the NHLBI WISE study. Am Heart J. 2001;141(5):735–41.

    Article  CAS  PubMed  Google Scholar 

  6. Crea F, Camici PG, Bairey Merz CN. Coronary microvascular dysfunction: an update. Eur Heart J. 2014;35(17):1101–11.

    Article  PubMed  Google Scholar 

  7. Gebhard C, Fiechter M, Herzog BA, Lohmann C, Bengs S, Treyer V, et al. Sex differences in the long-term prognostic value of (13)N-ammonia myocardial perfusion positron emission tomography. Eur J Nucl Med Mol Imaging. 2018;45(11):1964–1974.

  8. Wilkinson C, Bebb O, Dondo TB, Munyombwe T, Casadei B, Clarke S, et al. Sex differences in quality indicator attainment for myocardial infarction: a nationwide cohort study. Heart. 2018;105(7):516–523.

  9. Mieres JH, Gulati M, Bairey Merz N, Berman DS, Gerber TC, Hayes SN, et al. Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease: a consensus statement from the American Heart Association. Circulation. 2014;130(4):350–79.

    Article  PubMed  Google Scholar 

  10. Burger IA, Lohmann C, Messerli M, Bengs S, Becker A, Marędziak M, et al. Age- and sex-dependent changes in sympathetic activity of the left ventricular apex assessed by 18F-DOPA PET imaging. PLoS One. 2018;13(8):e0202302.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Templin C, Ghadri JR, Diekmann J, Napp LC, Bataiosu DR, Jaguszewski M, et al. Clinical features and outcomes of Takotsubo (stress) cardiomyopathy. N Engl J Med. 2015;373(10):929–38.

    Article  CAS  PubMed  Google Scholar 

  12. La Rovere MT, Bigger JT Jr, Marcus FI, Mortara A, Schwartz PJ. Baroreflex sensitivity and heart-rate variability in prediction of total cardiac mortality after myocardial infarction. ATRAMI (autonomic tone and reflexes after myocardial infarction) investigators. Lancet. 1998;351(9101):478–84.

    Article  PubMed  Google Scholar 

  13. Hedqvist P, Fredholm BB. Inhibitory effect of adenosine on adrenergic neuroeffector transmission in the rabbit heart. Acta Physiol Scand. 1979;105(1):120–2.

    Article  CAS  PubMed  Google Scholar 

  14. Hage FG, Heo J, Franks B, Belardinelli L, Blackburn B, Wang W, et al. Differences in heart rate response to adenosine and regadenoson in patients with and without diabetes mellitus. Am Heart J. 2009;157(4):771–6.

    Article  CAS  PubMed  Google Scholar 

  15. Fiechter M, Gebhard C, Ghadri JR, Fuchs TA, Pazhenkottil AP, Nkoulou RN, et al. Myocardial perfusion imaging with 13N-ammonia PET is a strong predictor for outcome. Int J Cardiol. 2013;167(3):1023–6.

    Article  PubMed  Google Scholar 

  16. Herzog BA, Husmann L, Valenta I, Gaemperli O, Siegrist PT, Tay FM, et al. Long-term prognostic value of 13N-ammonia myocardial perfusion positron emission tomography added value of coronary flow reserve. J Am Coll Cardiol. 2009;54(2):150–6.

    Article  PubMed  Google Scholar 

  17. Murthy VL, Naya M, Foster CR, Hainer J, Gaber M, Di Carli G, et al. Improved cardiac risk assessment with noninvasive measures of coronary flow reserve. Circulation. 2011;124(20):2215–24.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Hage FG, Dean P, Iqbal F, Heo J, Iskandrian AE. A blunted heart rate response to regadenoson is an independent prognostic indicator in patients undergoing myocardial perfusion imaging. J Nucl Cardiol. 2011;18(6):1086–94.

    Article  PubMed  Google Scholar 

  19. Bhatheja R, Francis GS, Pothier CE, Lauer MS. Heart rate response during dipyridamole stress as a predictor of mortality in patients with normal myocardial perfusion and normal electrocardiograms. Am J Cardiol. 2005;95(10):1159–64.

    Article  PubMed  Google Scholar 

  20. Abidov A, Hachamovitch R, Hayes SW, Ng CK, Cohen I, Friedman JD, et al. Prognostic impact of hemodynamic response to adenosine in patients older than age 55 years undergoing vasodilator stress myocardial perfusion study. Circulation. 2003;107(23):2894–9.

    Article  PubMed  Google Scholar 

  21. Amanullah AM, Berman DS, Erel J, Kiat H, Cohen I, Germano G, et al. Incremental prognostic value of adenosine myocardial perfusion single-photon emission computed tomography in women with suspected coronary artery disease. Am J Cardiol. 1998;82(6):725–30.

    Article  CAS  PubMed  Google Scholar 

  22. Gebhard C, Messerli M, Lohmann C, Treyer V, Bengs S, Benz DC, et al. Sex and age differences in the association of heart rate responses to adenosine and myocardial ischemia in patients undergoing myocardial perfusion imaging. J Nucl Cardiol. 2018.

  23. Bravo PE, Hage FG, Woodham RM, Heo J, Iskandrian AE. Heart rate response to adenosine in patients with diabetes mellitus and normal myocardial perfusion imaging. Am J Cardiol. 2008;102(8):1103–6.

    Article  CAS  PubMed  Google Scholar 

  24. Ogilby JD, Iskandrian AS, Untereker WJ, Heo J, Nguyen TN, Mercuro J. Effect of intravenous adenosine infusion on myocardial perfusion and function. Hemodynamic/angiographic and scintigraphic study. Circulation. 1992;86(3):887–95.

    Article  CAS  PubMed  Google Scholar 

  25. Vashist A, Heller EN, Blum S, Brown EJ, Bhalodkar NC. Association of heart rate response with scan and left ventricular function on adenosine myocardial perfusion imaging. Am J Cardiol. 2002;89(2):174–7.

    Article  PubMed  Google Scholar 

  26. Johnston DL, Daley JR, Hodge DO, Hopfenspirger MR, Gibbons RJ. Hemodynamic responses and adverse effects associated with adenosine and dipyridamole pharmacologic stress testing: a comparison in 2,000 patients. Mayo Clin Proc. 1995;70(4):331–6.

    Article  CAS  PubMed  Google Scholar 

  27. Conradson TB, Clarke B, Dixon CM, Dalton RN, Barnes PJ. Effects of adenosine on autonomic control of heart rate in man. Acta Physiol Scand. 1987;131(4):525–31.

    Article  CAS  PubMed  Google Scholar 

  28. Tenan MS, Brothers RM, Tweedell AJ, Hackney AC, Griffin L. Changes in resting heart rate variability across the menstrual cycle. Psychophysiology. 2014;51(10):996–1004.

    Article  PubMed  Google Scholar 

  29. Vongpatanasin W, Tuncel M, Mansour Y, Arbique D, Victor RG. Transdermal estrogen replacement therapy decreases sympathetic activity in postmenopausal women. Circulation. 2001;103(24):2903–8.

    Article  CAS  PubMed  Google Scholar 

  30. Liu CC, Kuo TB, Yang CC. Effects of estrogen on gender-related autonomic differences in humans. Am J Physiol Heart Circ Physiol. 2003;285(5):H2188–93.

    Article  CAS  PubMed  Google Scholar 

  31. Dean J, Cruz SD, Mehta PK, Merz CN. Coronary microvascular dysfunction: sex-specific risk, diagnosis, and therapy. Nat Rev Cardiol. 2015;12(7):406–14.

    Article  PubMed  Google Scholar 

  32. Pepine CJ, Anderson RD, Sharaf BL, Reis SE, Smith KM, Handberg EM, et al. Coronary microvascular reactivity to adenosine predicts adverse outcome in women evaluated for suspected ischemia results from the National Heart, lung and blood institute WISE (Women’s ischemia syndrome evaluation) study. J Am Coll Cardiol. 2010;55(25):2825–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Tomiyama T, Kumita S, Ishihara K, Suda M, Sakurai M, Hakozaki K, et al. Patients with reduced heart rate response to adenosine infusion have low myocardial flow reserve in (13)N-ammonia PET studies. Int J Cardiovasc Imaging. 2015;31(5):1089–95.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Haider A, Bengs S, Marędziak M, Messerli M, Fiechter M, Giannopoulos AA, et al. Heart rate reserve during pharmacological stress is a significant negative predictor of impaired coronary flow reserve in women. Eur J Nucl Med Mol Imaging. 2019;46(6):1257–1267.

  35. Zaffalon Junior JR, Viana AO, de Melo GEL, De Angelis K. The impact of sedentarism on heart rate variability (HRV) at rest and in response to mental stress in young women. Physiol Rep. 2018;6(18):e13873.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hachamovitch R, Berman DS, Shaw LJ, Kiat H, Cohen I, Cabico JA, et al. Incremental prognostic value of myocardial perfusion single photon emission computed tomography for the prediction of cardiac death: differential stratification for risk of cardiac death and myocardial infarction. Circulation. 1998;97(6):535–43.

    Article  CAS  PubMed  Google Scholar 

  37. Chareonthaitawee P, Kaufmann PA, Rimoldi O, Camici PG. Heterogeneity of resting and hyperemic myocardial blood flow in healthy humans. Cardiovasc Res. 2001;50(1):151–61.

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

CG was supported by grants from the Swiss National Science Foundation (SNSF), the Olga Mayenfisch Foundation, Switzerland, the OPO Foundation, Switzerland, the Novartis Foundation, Switzerland, the Swissheart Foundation, and the Helmut Horten Foundation, Switzerland. MM was supported by the Iten-Kohaut Foundation, Switzerland.

Author information

Author notes

  1. Caroline E. Gebhard and Monika Marędziak contributed equally to this work.

Authors and Affiliations

  1. Department of Nuclear Medicine, University Hospital Zurich, Raemistrasse 100, 8091, Zurich, Switzerland

    Caroline E. Gebhard, Monika Marędziak, Angela Portmann, Susan Bengs, Ahmed Haider, Michael Fiechter, Bernhard A. Herzog, Michael Messerli, Valerie Treyer, Ken Kudura, Elia von Felten, Dominik C. Benz, Tobias A. Fuchs, Christoph Gräni, Aju P. Pazhenkottil, Ronny R. Buechel, Philipp A. Kaufmann & Catherine Gebhard

  2. Department of Anesthesiology, University Hospital Basel, Basel, Switzerland

    Caroline E. Gebhard

  3. Center for Molecular Cardiology, University of Zurich, Zurich, Switzerland

    Monika Marędziak, Angela Portmann, Susan Bengs, Ahmed Haider, Michael Fiechter & Catherine Gebhard

Authors
  1. Caroline E. Gebhard
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Monika Marędziak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Angela Portmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Susan Bengs
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ahmed Haider
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael Fiechter
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Bernhard A. Herzog
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Michael Messerli
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Valerie Treyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Ken Kudura
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Elia von Felten
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Dominik C. Benz
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Tobias A. Fuchs
    View author publications

    You can also search for this author in PubMed Google Scholar

  14. Christoph Gräni
    View author publications

    You can also search for this author in PubMed Google Scholar

  15. Aju P. Pazhenkottil
    View author publications

    You can also search for this author in PubMed Google Scholar

  16. Ronny R. Buechel
    View author publications

    You can also search for this author in PubMed Google Scholar

  17. Philipp A. Kaufmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  18. Catherine Gebhard
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Catherine Gebhard.

Ethics declarations

Conflict of interest

All authors have the following to disclose: The University Hospital of Zurich holds a research contract with GE Healthcare. CG has received research grants from the Novartis Foundation, Switzerland.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

The study was approved by the local ethics committee (BASEC No. 2017–01112). The need for informed written consent was waived by the ethics committee.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Cardiology

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gebhard, C.E., Marędziak, M., Portmann, A. et al. Heart rate reserve is a long-term risk predictor in women undergoing myocardial perfusion imaging. Eur J Nucl Med Mol Imaging 46, 2032–2041 (2019). https://doi.org/10.1007/s00259-019-04344-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00259-019-04344-1

Keywords

Search

Navigation