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Confirmation of maximal hyperemia by the incremental dose of intracoronary papaverine


We investigated the effect of the papaverine dose increment method to confirm maximal hyperemia for fractional flow reserve (FFR) measurements. We evaluated 115 consecutive patients involving 200 lesions. FFR was measured after intracoronary papaverine injection into the left (12 mg) and right (8 mg) coronary arteries as standard doses. Except for 2 patients who had ventricular tachyarrythmia (VTA), we administered a higher papaverine dose (2 mg added to the standard dose). We compared the FFR values after using different papaverine doses. VTA incidence and electrocardiogram parameters were compared according to the papaverine doses used. The QTU interval and corrected QTU were significantly prolonged after using a higher dose compared with a standard dose. VTA occurred in one patient (0.9%) at the higher dose. There was no significant difference with a strong correlation between the FFR values in the 2 doses (r = 0.963, P < 0.001). Maximal hyperemia was achieved in most patients at the standard papaverine dose. However, 19 lesions changed ischemic diagnosis at the higher dose (12 lesions changed from ischemia negative to positive, and 7 lesions changed from positive to negative). Therefore, to confirm the appropriate ischemia diagnosis for borderline FFR values, it may be favorable to perform another FFR measurement at an incremental papaverine dose.

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  1. 1.

    Marie PY, Danchin N, Durand JF, Feldmann L, Grentzinger A, Olivier P, et al. Long-term prediction of major ischemic events by exercise thallium-201 single-photon emission computed tomography. Incremental prognostic value compared with clinical, exercise testing, catheterization and radionuclide angiographic data. J Am Coll Cardiol 1995;26: 879–886.

  2. 2.

    Pijls NH, van Schaardenburgh P, Manoharan G, Boersma E, Bech JW, van't Veer M, et al. Percutaneous coronary intervention of functionally nonsignificant stenosis: 5-year follow-up of the DEFER Study. J Am Coll Cardiol 2007;49: 2105–2111.

  3. 3.

    Task Force M, Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, et al. ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J. 2013;34:2949–3003.

    Article  Google Scholar 

  4. 4.

    Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van' t Veer M, et al. Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 2009;360: 213–224.

  5. 5.

    Johnson NP, Johnson DT, Kirkeeide RL, Berry C, De Bruyne B, Fearon WF, et al. Repeatability of fractional flow reserve despite variations in systemic and coronary hemodynamics. JACC Cardiovasc Interv. 2015;8:1018–27.

    Article  Google Scholar 

  6. 6.

    Nishi T, Kitahara H, Iwata Y, Fujimoto Y, Nakayama T, Takahara M, et al. Efficacy of combined administration of intracoronary papaverine plus intravenous adenosine 5'-triphosphate in assessment of fractional flow reserve. J Cardiol. 2016;68:512–6.

    Article  Google Scholar 

  7. 7.

    Nakayama M, Chikamori T, Uchiyama T, Kimura Y, Hijikata N, Ito R, et al. Effects of caffeine on fractional flow reserve values measured using intravenous adenosine triphosphate. Cardiovasc Interv Ther. 2018;33:116–24.

    CAS  Article  Google Scholar 

  8. 8.

    Nakayama M, Tanaka N, Sakoda K, Hokama Y, Hoshino K, Kimura Y, et al. Papaverine-induced polymorphic ventricular tachycardia during coronary flow reserve study of patients with moderate coronary artery disease. Circ J. 2015;79:530–6.

    Article  Google Scholar 

  9. 9.

    Nakayama M, Saito A, Kitazawa H, Takahashi M, Sato M, Fuse K, et al. Papaverine-induced polymorphic ventricular tachycardia in relation to QTU and giant T–U waves in four cases. Intern Med. 2012;51:351–6.

    CAS  Article  Google Scholar 

  10. 10.

    Pijls NH. Fractional flow reserve to guide coronary revascularization. Circ J. 2013;77:561–9.

    Article  Google Scholar 

  11. 11.

    American DA. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2012;35(Suppl 1):S64–71.

    Article  Google Scholar 

  12. 12.

    Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M, et al. ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J. 2013;34:2159–219.

    Article  Google Scholar 

  13. 13.

    Teramoto T, Sasaki J, Ishibashi S, Birou S, Daida H, Dohi S, et al. Cardiovascular disease risk factors other than dyslipidemia. Executive summary of the Japan Atherosclerosis Society (JAS) guidelines for the diagnosis and prevention of atherosclerotic cardiovascular diseases in Japan - 2012 version. J Atheroscler Thromb 2013;20: 733–742.

  14. 14.

    Pijls NH, Sels JW. Functional measurement of coronary stenosis. J Am Coll Cardiol. 2012;59:1045–57.

    Article  Google Scholar 

  15. 15.

    Lim WH, Koo BK, Nam CW, Doh JH, Park JJ, Yang HM, et al. Variability of fractional flow reserve according to the methods of hyperemia induction. Catheter Cardiovasc Interv. 2015;85:970–6.

    Article  Google Scholar 

  16. 16.

    Zhang X, Shen W, Cai X, Zheng A. Polymorphous ventricular tachycardia after intracoronary papaverine: a report of 3 cases. Chin Med Sci J. 1993;8:248–9.

    CAS  PubMed  Google Scholar 

  17. 17.

    Talman CL, Winniford MD, Rossen JD, Simonetti I, Kienzle MG, Marcus ML. Polymorphous ventricular tachycardia: a side effect of intracoronary papaverine. J Am Coll Cardiol. 1990;15:275–8.

    CAS  Article  Google Scholar 

  18. 18.

    Vrolix M, Piessens J, Geest HD. Torsades de pointes after intracoronary papaverine. Eur Heart J 1991; 12: 273–276.

  19. 19.

    Inoue T, Asahi S, Takayanagi K, Morooka S, Takabatake Y. QT Prolongation and possibility of ventricular arrhythmias after intracoronary papaverine. Cardiology. 1994;84:9–13.

    CAS  Article  Google Scholar 

  20. 20.

    Jain A, Jenkins MG. Intracoronary electrocardiogram during torsade des pointes secondary to intracoronary papaverine. Cathet Cardiovasc Diagn. 1989;18:255–7.

    CAS  Article  Google Scholar 

  21. 21.

    Wilson RF, White CW. Serious ventricular dysrhythmias after intracoronary papaverine. Am J Cardiol. 1988;62:1301–2.

    CAS  Article  Google Scholar 

  22. 22.

    Kern MJ, Deligonul U, Serota H, Gudipati C, Buckingham T. Ventricular arrhythmia due to intracoronary papaverine: analysis of QT intervals and coronary vasodilatory reserve. Cathet Cardiovasc Diagn. 1990;19:229–36.

    CAS  Article  Google Scholar 

  23. 23.

    Kirchhof P, Franz MR, Bardai A, Wilde AM. Giant T-U waves precede torsades de pointes in long QT syndrome: a systematic electrocardiographic analysis in patients with acquired and congenital QT prolongation. J Am Coll Cardiol. 2009;54:143–9.

    Article  Google Scholar 

  24. 24.

    Habbab MdA, El-Sherie N. Drug-induced torsades de pointes: role of early afterdepolarizations and dispersion of repolarization. Am J Med 1990;89: 241–246.

  25. 25.

    Shimizu W, Ohe T, Kurita T, Tokuda T, Shimomura K. Epinephrine-induced ventricular premature complexes due to early afterdepolarizations and effects of verapamil and propranolol in a patient with congenital long QT syndrome. J Cardiovasc Electrophysiol. 1994;5:438–44.

    CAS  Article  Google Scholar 

  26. 26.

    Jackman WM, Friday KJ, Anderson JL, Aliot EM, Clark M, Lazzara R. The long QT syndromes: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis. 1988;31:115–72.

    CAS  Article  Google Scholar 

  27. 27.

    Trinkley KE, Page RL 2nd, Lien H, Yamanouye K, Tisdale JE. QT interval prolongation and the risk of torsades de pointes: essentials for clinicians. Curr Med Res Opin. 2013;29:1719–26.

    Article  Google Scholar 

  28. 28.

    Yoshida H, Horie M, Otani H, Kawashima T, Onishi Y, Sasayama S. Bradycardia-induced long QT syndrome caused by a de novo missense mutation in the S2–S3 inner loop of HERG. Am J Med Genet. 2001;98:348–52.

    CAS  Article  Google Scholar 

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Correspondence to Masafumi Nakayama.

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T.N. serves as a consultant for St. Jude Medical, Philips Volcano Japan, and Boston Scientific. The other authors report no relationships that could be construed as a conflict of interest.

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Nakayama, M., Tanaka, N., Yamashita, J. et al. Confirmation of maximal hyperemia by the incremental dose of intracoronary papaverine. Cardiovasc Interv and Ther 35, 371–378 (2020).

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  • Factional flow reserve
  • Coronary circulation
  • Papaverine
  • QT interval
  • Ventricular tachyarrhythmia