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Heart rate reserve during pharmacological stress is a significant negative predictor of impaired coronary flow reserve in women

  • Ahmed Haider
  • Susan Bengs
  • Monika Maredziak
  • Michael Messerli
  • Michael Fiechter
  • Andreas A. Giannopoulos
  • Valerie Treyer
  • Moritz Schwyzer
  • Christel Hermann Kamani
  • Dimitri Patriki
  • Elia von Felten
  • Dominik C. Benz
  • Tobias A. Fuchs
  • Christoph Gräni
  • Aju P. Pazhenkottil
  • Philipp A. Kaufmann
  • Ronny R. Buechel
  • Catherine GebhardEmail author
Original Article
  • 53 Downloads

Abstract

Purpose

Evidence to date has failed to adequately explore determinants of cardiovascular risk in women with coronary microvascular dysfunction (CMVD). Heart rate responses to adenosine mirror autonomic activity and may carry important prognostic information for the diagnosis of CMVD.

Methods

Hemodynamic changes during adenosine stress were analyzed in a propensity-matched cohort of 404 patients (202 women, mean age 65.9 ± 11.0) who underwent clinically indicated myocardial perfusion 13N-ammonia Positron-Emission-Tomography (PET) at our institution between September 2013 and May 2017.

Results

Baseline heart rate (HR) was significantly higher in patients with abnormal coronary flow reserve (CFR, p < 0.001 vs normal CFR). Accordingly, a blunted HR response to adenosine (=reduced heart rate reserve, %HRR) was seen in patients with abnormal CFR, with a most pronounced effect being observed in female patients free of myocardial ischemia (45.9 ± 34.9 vs 26.5 ± 18.0, p < 0.001 in women and 29.1 ± 16.9 vs 24.3 ± 21.7, p = 0.15 in men). Hence, a fully-adjusted multivariate logistic regression model identified HRR as the strongest negative predictor of reduced CFR in women free of myocardial ischemia, but not in men. Accordingly, receiver operating characteristics (ROC) curves for the presence of reduced CFR revealed that a %HRR <35 was a powerful predictor for abnormal CFR with a sensitivity of 81% and a specificity of 60% in women.

Conclusion

A blunted HRR <35% is associated with abnormal CFR in women. Taking into account HR responses during stress test in women may help to risk stratify the heterogeneous female population of patients with non-obstructive coronary artery disease (CAD).

Keywords

13N-ammonia PET Coronary artery disease Women Adenosine Heart rate reserve 

Notes

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.

Compliance with ethical standards

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

Our study was approved by the Cantonal Ethics Board in Zurich, Switzerland (BASEC No. 2017–01112). The need to obtain informed consent was waived by the ethics committee due to the retrospective nature of the study.

References

  1. 1.
    Townsend N, Wilson L, Bhatnagar P, Wickramasinghe K, Rayner M, Nichols M. Cardiovascular disease in Europe: epidemiological update 2016. Eur Heart J. 2016;37(42):3232–45.CrossRefGoogle Scholar
  2. 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.CrossRefGoogle Scholar
  3. 3.
    Mieres JH, Shaw LJ, Arai A, Budoff MJ, Flamm SD, Hundley WG, et al. Role of noninvasive testing in the clinical evaluation of women with suspected coronary artery disease: consensus statement from the cardiac imaging committee, council on clinical cardiology, and the cardiovascular imaging and intervention committee, council on cardiovascular radiology and intervention, American Heart Association. Circulation. 2005;111(5):682–96.CrossRefGoogle Scholar
  4. 4.
    Baldassarre LA, Raman SV, Min JK, Mieres JH, Gulati M, Wenger NK, et al. Noninvasive imaging to evaluate women with stable ischemic heart disease. J Am Coll Cardiol Img. 2016;9(4):421–35.CrossRefGoogle Scholar
  5. 5.
    Gianrossi R, Detrano R, Mulvihill D, Lehmann K, Dubach P, Colombo A, et al. Exercise-induced ST depression in the diagnosis of coronary artery disease. A meta-analysis. Circulation. 1989;80(1):87–98.CrossRefGoogle Scholar
  6. 6.
    Botvinick EH. Breast attenuation artifacts in Tl-201 scintigraphy. Radiology. 1988;168(3):878–9.PubMedGoogle Scholar
  7. 7.
    Hansen CL, Crabbe D, Rubin S. Lower diagnostic accuracy of thallium-201 SPECT myocardial perfusion imaging in women: an effect of smaller chamber size. J Am Coll Cardiol. 1996;28(5):1214–9.CrossRefGoogle Scholar
  8. 8.
    Sanders GD, Patel MR, Chatterjee R, Ross AK, Bastian LA, Coeytaux RR, et al. AHRQ future research needs papers. Noninvasive technologies for the diagnosis of coronary artery disease in women: future research needs: identification of future research needs from comparative effectiveness review no 58. Rockville: Agency for Healthcare Research and Quality (US); 2013.Google Scholar
  9. 9.
    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.CrossRefGoogle Scholar
  10. 10.
    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.CrossRefGoogle Scholar
  11. 11.
    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.CrossRefGoogle Scholar
  12. 12.
    Sedlak TL, Lee M, Izadnegahdar M, Merz CN, Gao M, Humphries KH. Sex differences in clinical outcomes in patients with stable angina and no obstructive coronary artery disease. Am Heart J. 2013;166(1):38–44.CrossRefGoogle Scholar
  13. 13.
    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.CrossRefGoogle Scholar
  14. 14.
    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.CrossRefGoogle Scholar
  15. 15.
    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.CrossRefGoogle Scholar
  16. 16.
    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.Google Scholar
  17. 17.
    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 Apr 23.  https://doi.org/10.1007/s12350-018-1276-x.
  18. 18.
    Dorbala S, Di Carli MF, Delbeke D, Abbara S, DePuey EG, Dilsizian V, et al. SNMMI/ASNC/SCCT guideline for cardiac SPECT/CT and PET/CT 1.0. J Nucl Med. 2013;54(8):1485–507.CrossRefGoogle Scholar
  19. 19.
    Reyes E, Stirrup J, Roughton M, D’Souza S, Underwood SR, Anagnostopoulos C. Attenuation of adenosine-induced myocardial perfusion heterogeneity by atenolol and other cardioselective beta-adrenoceptor blockers: a crossover myocardial perfusion imaging study. J Nucl Med. 2010;51(7):1036–43.CrossRefGoogle Scholar
  20. 20.
    Hendel RC, Berman DS, Di Carli MF, Heidenreich PA, Henkin RE, Pellikka PA, et al. ACCF/ASNC/ACR/AHA/ASE/SCCT/SCMR/SNM 2009 appropriate use criteria for cardiac radionuclide imaging: a report of the American College of Cardiology Foundation appropriate use criteria task force, the American Society of Nuclear Cardiology, the American College of Radiology, the American Heart Association, the American Society of Echocardiography, the Society of Cardiovascular Computed Tomography, the Society for Cardiovascular Magnetic Resonance, and the Society of Nuclear Medicine. Circulation. 2009;119(22):e561–87.PubMedGoogle Scholar
  21. 21.
    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.CrossRefGoogle Scholar
  22. 22.
    Joutsiniemi E, Saraste A, Pietila M, Maki M, Kajander S, Ukkonen H, et al. Absolute flow or myocardial flow reserve for the detection of significant coronary artery disease? Eur Heart J Cardiovasc Imaging. 2014;15(6):659–65.CrossRefGoogle Scholar
  23. 23.
    Phelps ME. Positron emission tomography provides molecular imaging of biological processes. Proc Natl Acad Sci USA. 2000;97(16):9226–33.CrossRefGoogle Scholar
  24. 24.
    Nakazato R, Berman DS, Alexanderson E, Slomka P. Myocardial perfusion imaging with PET. Imaging Med. 2013;5(1):35–46.CrossRefGoogle Scholar
  25. 25.
    Nandalur KR, Dwamena BA, Choudhri AF, Nandalur SR, Reddy P, Carlos RC. Diagnostic performance of positron emission tomography in the detection of coronary artery disease: a meta-analysis. Acad Radiol. 2008;15(4):444–51.CrossRefGoogle Scholar
  26. 26.
    Jaarsma C, Leiner T, Bekkers SC, Crijns HJ, Wildberger JE, Nagel E, et al. Diagnostic performance of noninvasive myocardial perfusion imaging using single-photon emission computed tomography, cardiac magnetic resonance, and positron emission tomography imaging for the detection of obstructive coronary artery disease: a meta-analysis. J Am Coll Cardiol. 2012;59(19):1719–28.CrossRefGoogle Scholar
  27. 27.
    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.CrossRefGoogle Scholar
  28. 28.
    Amanullah AM, Berman DS, Hachamovitch R, Kiat H, Kang X, Friedman JD. Identification of severe or extensive coronary artery disease in women by adenosine technetium-99m sestamibi SPECT. Am J Cardiol. 1997;80(2):132–7.CrossRefGoogle Scholar
  29. 29.
    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.CrossRefGoogle Scholar
  30. 30.
    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.CrossRefGoogle Scholar
  31. 31.
    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.CrossRefGoogle Scholar
  32. 32.
    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.CrossRefGoogle Scholar
  33. 33.
    Hage FG, Perry G, Heo J, Iskandrian AE. Blunting of the heart rate response to adenosine and regadenoson in relation to hyperglycemia and the metabolic syndrome. Am J Cardiol. 2010;105(6):839–43.CrossRefGoogle Scholar
  34. 34.
    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.CrossRefGoogle Scholar
  35. 35.
    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 Card Imaging. 2015;31(5):1089–95.CrossRefGoogle Scholar
  36. 36.
    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.CrossRefGoogle Scholar
  37. 37.
    Burger IA, Lohmann C, Messerli M, Bengs S, Becker A, Maredziak 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.CrossRefGoogle Scholar
  38. 38.
    Agrawal S, Mehta PK, Bairey Merz CN. Cardiac syndrome X: update. Heart Fail Clin. 2016;12(1):141–56.CrossRefGoogle Scholar
  39. 39.
    Camici PG, Marraccini P, Lorenzoni R, Buzzigoli G, Pecori N, Perissinotto A, et al. Coronary hemodynamics and myocardial metabolism in patients with syndrome X: response to pacing stress. J Am Coll Cardiol. 1991;17(7):1461–70.CrossRefGoogle Scholar
  40. 40.
    Tousoulis D, Crake T, Lefroy DC, Galassi AR, Maseri A. Left ventricular hypercontractility and ST segment depression in patients with syndrome X. J Am Coll Cardiol. 1993;22(6):1607–13.CrossRefGoogle Scholar
  41. 41.
    Kaski JC. Cardiac syndrome X in women: the role of oestrogen deficiency. Heart. 2006;92(Suppl 3):iii5–9.PubMedPubMedCentralGoogle Scholar
  42. 42.
    Montorsi P, Fabbiocchi F, Loaldi A, Annoni L, Polese A, De Cesare N, et al. Coronary adrenergic hyperreactivity in patients with syndrome X and abnormal electrocardiogram at rest. Am J Cardiol. 1991;68(17):1698–703.CrossRefGoogle Scholar
  43. 43.
    Gulli G, Cemin R, Pancera P, Menegatti G, Vassanelli C, Cevese A. Evidence of parasympathetic impairment in some patients with cardiac syndrome X. Cardiovasc Res. 2001;52(2):208–16.CrossRefGoogle Scholar
  44. 44.
    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.CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Ahmed Haider
    • 1
    • 2
  • Susan Bengs
    • 1
    • 2
  • Monika Maredziak
    • 1
    • 2
  • Michael Messerli
    • 1
  • Michael Fiechter
    • 1
    • 2
  • Andreas A. Giannopoulos
    • 1
  • Valerie Treyer
    • 1
  • Moritz Schwyzer
    • 1
  • Christel Hermann Kamani
    • 1
  • Dimitri Patriki
    • 1
  • Elia von Felten
    • 1
  • Dominik C. Benz
    • 1
  • Tobias A. Fuchs
    • 1
  • Christoph Gräni
    • 1
  • Aju P. Pazhenkottil
    • 1
  • Philipp A. Kaufmann
    • 1
  • Ronny R. Buechel
    • 1
  • Catherine Gebhard
    • 1
    • 2
    Email author
  1. 1.Department of Nuclear MedicineUniversity Hospital ZurichZurichSwitzerland
  2. 2.Center for Molecular CardiologyUniversity of ZurichZurichSwitzerland

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