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Sex differences in the long-term prognostic value of 13N-ammonia myocardial perfusion positron emission tomography

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Abstract

Purpose

Evidence to date on the unique female determinants of cardiovascular risk is inadequate. Positron Emission Tomography (PET) is considered to have the highest accuracy for the assessment of myocardial perfusion in patients with suspected coronary artery disease (CAD), but its long-term prognostic accuracy in women has not been established.

Methods

A total of 619 consecutive patients (138 women, mean age 60.0 ± 11.8 years) underwent clinically indicated 13N-ammonia PET at our institution and were followed up (median 5.7 years) for major adverse cardiovascular events (MACE) including cardiac death, nonfatal myocardial infarction, hospitalization for any cardiac reason and late revascularization.

Results

During follow-up, 271 patients had at least one cardiac event, including 64 cardiac deaths and 33 nonfatal myocardial infarctions. In both women and men, abnormal myocardial perfusion was associated with reduced event-free survival (log rank p < 0.001). In women, abnormal myocardial perfusion was associated with a higher risk of a worse outcome than in men (adjusted HR 4.1, 95% CI 1.8–9.0 in women; HR 2.4, 95% CI 1.5–3.8 in men; pinteraction < 0.001). In contrast, abnormal coronary flow reserve (CFR) was a significant predictor of 10-year MACE in men (p = 0.006) but not in women (p = NS). Accordingly, an interaction term of sex and abnormal myocardial perfusion or CFR was significant (p < 0.001).

Conclusion

While perfusion findings in 13N-ammonia PET provide effective risk stratification in women and men, CFR adds incremental prognostic value for long-term cardiac outcomes only in men. Refined strategies in noninvasive imaging are needed in women to improve CAD risk prediction.

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References

  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. https://doi.org/10.1093/eurheartj/ehw334.

    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. https://doi.org/10.1161/CIRCULATIONAHA.115.015293.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 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. https://doi.org/10.1161/CIR.0000000000000061.

    Article  PubMed  Google Scholar 

  4. 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.

    Article  PubMed  CAS  Google Scholar 

  5. Baldassarre LA, Raman SV, Min JK, Mieres JH, Gulati M, Wenger NK, et al. Noninvasive imaging to evaluate women with stable ischemic heart disease. JACC Cardiovasc Imaging. 2016;9(4):421–35. https://doi.org/10.1016/j.jcmg.2016.01.004.

    Article  PubMed  PubMed Central  Google Scholar 

  6. 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. https://doi.org/10.1016/j.jacc.2015.08.876.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Sanders GD, Patel MR, Chatterjee R, Ross AK, Bastian LA, Coeytaux RR, et al. 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, MD: Agency for Healthcare Research and Quality (US); 2013.

  8. Botvinick EH. Breast attenuation artifacts in Tl-201 scintigraphy. Radiology. 1988;168(3):878–9. https://doi.org/10.1148/radiology.168.3.878-c.

    Article  PubMed  CAS  Google Scholar 

  9. 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. https://doi.org/10.1016/s0735-1097(96)00304-x.

    Article  PubMed  CAS  Google Scholar 

  10. 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. https://doi.org/10.1016/j.acra.2007.08.012.

    Article  PubMed  Google Scholar 

  11. Kajander S, Joutsiniemi E, Saraste M, Pietila M, Ukkonen H, Saraste A, et al. Cardiac positron emission tomography/computed tomography imaging accurately detects anatomically and functionally significant coronary artery disease. Circulation. 2010;122(6):603–13. https://doi.org/10.1161/circulationaha.109.915009.

    Article  PubMed  CAS  Google Scholar 

  12. 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. https://doi.org/10.1016/j.jacc.2011.12.040.

    Article  PubMed  Google Scholar 

  13. 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. https://doi.org/10.1016/j.ijcard.2012.03.076.

    Article  PubMed  Google Scholar 

  14. 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. https://doi.org/10.1016/j.jacc.2009.02.069.

    Article  PubMed  Google Scholar 

  15. Bateman TM, Heller GV, McGhie AI, Friedman JD, Case JA, Bryngelson JR, et al. Diagnostic accuracy of rest/stress ECG-gated Rb-82 myocardial perfusion PET: comparison with ECG-gated Tc-99m sestamibi SPECT. J Nucl Cardiol. 2006;13(1):24–33. https://doi.org/10.1016/j.nuclcard.2005.12.004.

    Article  PubMed  Google Scholar 

  16. Neglia D, Rovai D, Caselli C, Pietila M, Teresinska A, Aguade-Bruix S, et al. Detection of significant coronary artery disease by noninvasive anatomical and functional imaging. Circ Cardiovasc Imaging. 2015;8:e002179. https://doi.org/10.1161/circimaging.114.002179.

    Article  PubMed  Google Scholar 

  17. Kay J, Dorbala S, Goyal A, Fazel R, Di Carli MF, Einstein AJ, et al. Influence of sex on risk stratification with stress myocardial perfusion Rb-82 positron emission tomography: results from the PET (Positron Emission Tomography) Prognosis Multicenter Registry. J Am Coll Cardiol. 2013;62(20):1866–76. https://doi.org/10.1016/j.jacc.2013.06.017.

    Article  PubMed  Google Scholar 

  18. D’Agostino RB Sr, Vasan RS, Pencina MJ, Wolf PA, Cobain M, Massaro JM, et al. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation. 2008;117(6):743–53. https://doi.org/10.1161/circulationaha.107.699579.

    Article  PubMed  Google Scholar 

  19. 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. https://doi.org/10.1161/circulationaha.109.192519.

    Article  PubMed  Google Scholar 

  20. Nagamachi S, Czernin J, Kim AS, Sun KT, Bottcher M, Phelps ME, et al. Reproducibility of measurements of regional resting and hyperemic myocardial blood flow assessed with PET. J Nucl Med. 1996;37(10):1626–31.

    PubMed  CAS  Google Scholar 

  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. https://doi.org/10.1161/circulationaha.111.050427.

    Article  PubMed  PubMed Central  Google Scholar 

  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. https://doi.org/10.1093/ehjci/jet274.

    Article  PubMed  Google Scholar 

  23. Van Tosh A, Supino PG, Nichols KJ, Garza D, Horowitz SF, Reichek N. Prognosis of a normal positron emission tomography 82Rb myocardial perfusion imaging study in women with no history of coronary disease. Cardiology. 2010;117(4):301–6. https://doi.org/10.1159/000323841.

    Article  PubMed  Google Scholar 

  24. Shaw LJ, Bugiardini R, Merz CN. Women and ischemic heart disease: evolving knowledge. J Am Coll Cardiol. 2009;54(17):1561–75. https://doi.org/10.1016/j.jacc.2009.04.098.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Berman DS, Kang X, Hayes SW, Friedman JD, Cohen I, Abidov A, et al. Adenosine myocardial perfusion single-photon emission computed tomography in women compared with men. Impact of diabetes mellitus on incremental prognostic value and effect on patient management. J Am Coll Cardiol. 2003;41(7):1125–33.

    Article  PubMed  Google Scholar 

  26. Marwick TH, Shaw LJ, Lauer MS, Kesler K, Hachamovitch R, Heller GV, et al. The noninvasive prediction of cardiac mortality in men and women with known or suspected coronary artery disease. Economics of Noninvasive Diagnosis (END) Study Group. Am J Med. 1999;106(2):172–8.

    Article  PubMed  CAS  Google Scholar 

  27. Shaw LJ, Iskandrian AE. Prognostic value of gated myocardial perfusion SPECT. J Nucl Cardiol. 2004;11(2):171–85. https://doi.org/10.1016/j.nuclcard.2003.12.004.

    Article  PubMed  Google Scholar 

  28. 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. https://doi.org/10.1161/circulationaha.113.008507.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Johnson NP, Gould KL. Integrating noninvasive absolute flow, coronary flow reserve, and ischemic thresholds into a comprehensive map of physiological severity. JACC Cardiovasc Imaging. 2012;5(4):430–40. https://doi.org/10.1016/j.jcmg.2011.12.014.

    Article  PubMed  Google Scholar 

  30. Gould KL, Johnson NP, Bateman TM, Beanlands RS, Bengel FM, Bober R, et al. Anatomic versus physiologic assessment of coronary artery disease. Role of coronary flow reserve, fractional flow reserve, and positron emission tomography imaging in revascularization decision-making. J Am Coll Cardiol. 2013;62(18):1639–53. https://doi.org/10.1016/j.jacc.2013.07.076.

    Article  PubMed  Google Scholar 

  31. 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  PubMed  CAS  Google Scholar 

  32. Range FT, Kies P, Schafers KP, Breithardt G, Schober O, Wichter T, et al. Sex differences in absolute myocardial perfusion. Non-invasive H2(15)O-PET in young healthy adults. Nuklearmedizin. 2016;55(5):196–202. https://doi.org/10.3413/Nukmed-0821-16-04.

    Article  PubMed  Google Scholar 

  33. Momen A, Gao Z, Cohen A, Khan T, Leuenberger UA, Sinoway LI. Coronary vasoconstrictor responses are attenuated in young women as compared with age-matched men. J Physiol. 2010;588(Pt 20):4007–16. https://doi.org/10.1113/jphysiol.2010.192492.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Kim A, Deo SH, Vianna LC, Balanos GM, Hartwich D, Fisher JP, et al. Sex differences in carotid baroreflex control of arterial blood pressure in humans: relative contribution of cardiac output and total vascular conductance. Am J Physiol Heart Circ Physiol. 2011;301(6):H2454–65. https://doi.org/10.1152/ajpheart.00772.2011.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Heaps CL, Bowles DK. Gender-specific K(+)-channel contribution to adenosine-induced relaxation in coronary arterioles. J Appl Physiol (1985). 2002;92(2):550–8. https://doi.org/10.1152/japplphysiol.00566.2001.

    Article  CAS  Google Scholar 

  36. Vaccarino V, Wilmot K, Al Mheid I, Ramadan R, Pimple P, Shah AJ, et al. Sex differences in mental stress-induced myocardial ischemia in patients with coronary heart disease. J Am Heart Assoc. 2016;5:e003630. https://doi.org/10.1161/jaha.116.003630.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Eriksson BE, Tyni-Lenne R, Svedenhag J, Hallin R, Jensen-Urstad K, Jensen-Urstad M, et al. Physical training in syndrome X: physical training counteracts deconditioning and pain in syndrome X. J Am Coll Cardiol. 2000;36(5):1619–25.

    Article  PubMed  CAS  Google Scholar 

  38. Hambrecht R, Adams V, Erbs S, Linke A, Krankel N, Shu Y, et al. Regular physical activity improves endothelial function in patients with coronary artery disease by increasing phosphorylation of endothelial nitric oxide synthase. Circulation. 2003;107(25):3152–8. https://doi.org/10.1161/01.cir.0000074229.93804.5c.

    Article  PubMed  CAS  Google Scholar 

  39. Taqueti VR, Everett BM, Murthy VL, Gaber M, Foster CR, Hainer J, et al. Interaction of impaired coronary flow reserve and cardiomyocyte injury on adverse cardiovascular outcomes in patients without overt coronary artery disease. Circulation. 2015;131(6):528–35. https://doi.org/10.1161/circulationaha.114.009716.

    Article  PubMed  CAS  Google Scholar 

  40. Kaufmann PA, Gnecchi-Ruscone T, Yap JT, Rimoldi O, Camici PG. Assessment of the reproducibility of baseline and hyperemic myocardial blood flow measurements with 15O-labeled water and PET. J Nucl Med. 1999;40(11):1848–56.

    PubMed  CAS  Google Scholar 

  41. Manabe O, Yoshinaga K, Katoh C, Naya M, de Kemp RA, Tamaki N. Repeatability of rest and hyperemic myocardial blood flow measurements with 82Rb dynamic PET. J Nucl Med. 2009;50(1):68–71. https://doi.org/10.2967/jnumed.108.055673.

    Article  PubMed  Google Scholar 

  42. Sawada S, Muzik O, Beanlands RS, Wolfe E, Hutchins GD, Schwaiger M. Interobserver and interstudy variability of myocardial blood flow and flow-reserve measurements with nitrogen 13 ammonia-labeled positron emission tomography. J Nucl Cardiol. 1995;2(5):413–22.

    Article  PubMed  CAS  Google Scholar 

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Funding

This study was funded by the Swiss National Science Foundation (SNSF), the Olga Mayenfisch Foundation, Switzerland, the OPO Foundation, Switzerland, the Novartis Foundation, Switzerland, and the Swissheart Foundation (to C.G.).

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Authors and Affiliations

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

    Catherine Gebhard, Michael Fiechter, Bernhard A. Herzog, Christine Lohmann, Susan Bengs, Valerie Treyer, Michael Messerli, Dominik C. Benz, Andreas A. Giannopoulos, Christoph Gräni, Aju P. Pazhenkottil, Ronny R. Buechel & Philipp A. Kaufmann

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

    Catherine Gebhard, Christine Lohmann & Susan Bengs

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  1. Catherine Gebhard
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Correspondence to Catherine Gebhard.

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Ethical approval

Our study was approved by the Cantonal Ethics Board in Zurich, Switzerland (BASEC No. 2017–01112). All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards, and were conducted in accordance with institutional guidelines.

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Informed consent was obtained from all individual participants included in the study.

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Gebhard, C., Fiechter, M., Herzog, B.A. et al. Sex differences in the long-term prognostic value of 13N-ammonia myocardial perfusion positron emission tomography. Eur J Nucl Med Mol Imaging 45, 1964–1974 (2018). https://doi.org/10.1007/s00259-018-4046-8

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