Prognostic Value of Coronary Flow Reserve in Asymptomatic Moderate or Severe Aortic Stenosis with Preserved Ejection Fraction and Nonobstructed Coronary Arteries Banovic Marko, M.D., Ph.D.,*,† Vujisic-Tesic Bosiljka, M.D., Ph.D.,*,† Brkovic Voin, M.D.,† Petrovic Milan, M.D., Ph.D.,*,† Nedeljkovic Ivana, M.D., Ph.D.,*,† Popovic Dejana, M.D., Ph.D.,*,† Trifunovic Danijela, M.D., Ph.D.,*,† and Nikolic Serjan, Ph.D.‡ *Department of Cardiology, University Clinical Center of Serbia, Belgrade, Serbia; †Medical School, University of Belgrade, Belgrade, Serbia; and ‡Freelance scientist Aim: Patients with moderate and severe aortic stenosis (AS) and without obstructive epicardial coronary disease have been shown to have an impairment of coronary flow reserve (CFR). We investigated the prognostic significance of CFR in predicting death during mid-to-long-term follow-up in asymptomatic patients with moderate/severe AS, preserved ejection fraction (EF), and with nonobstructed coronary arteries. Method and Result: A total of 127 patients with moderate or severe AS (effective orifice area of 1.5 cm 2 or less), mean age 66 Æ 11 were enrolled in this prospective study. The median follow-up was 32 Æ 7 months. All patients had standard Doppler echo study, coronary angiography, and adenosine- stress transthoracic Doppler echo for CFR measurement. Univariate analysis showed that diabetes mell- itus, CFR, aortic valve area (AVA), maximal velocity (V max ), mean pressure gradient (P mean ), energy loss index (ELI), aortic valve resistance (AVR), NT-proBNP, E/E′, valvulo-arterial impedance (Z va ), and stroke work loss (SWL) were associated (P < 0.05) with death. Multivariable logistic regression analysis revealed that only Z va and CFR were independent predictors of death, with the CFR being the single strongest predictor (Table 2). Using receiver operating characteristics (ROC) analysis, the CFR value of 1.85 had the highest accuracy in predicting the death during mid-to-long-term follow-up (area under the curve; AUC 0.890, P = 0.009, sensitivity 96.3%, specificity 75%; 95% CI 0.287–0.946; Fig. 1). The Z va value of 5.52 Hg/mL per m had a sensitivity 70.0% and specificity 72.0% (AUC 0.766, 95% CI 0.587–0.946; P = 0.005). Conclusion: This study demonstrates that CFR has a prognostic value in patients with asymptomatic moderate or severe AS with preserved EF and nonobstructed coronary arteries. (Echocardiography 2014;31:428–433) Key words: aortic stenosis, coronary flow reserve, microcirculation, predictive value Transthoracic Doppler-derived coronary flow reserve (CFR) measurements have been used widely to evaluate both stenosed and nonob- structed epicardial coronary arteries, predomi- nantly in left anterior descending (LAD) artery distribution. 1,2 In the absence of obstructive epicardial coronary artery disease, measurement of CFR enables assessment of coronary microvas- cular function. 3 Aortic stenosis (AS) has now become the most frequent type of valvular heart disease in Europe and North America. 4 The outcome of even asymptomatic severe AS is not favorable, with reported average event-free survival at 3 years going to low 20%. 4,5 Asymptomatic patients with AS and without obstructive epicardial coro- nary disease may have impaired CFR, with the more severe AS the more impaired CFR. 6,7 This abnormality may be responsible for myocardial ischemia, and may be associated with major adverse cardiac event (MACE), especially after the onset of angina-like symptom. 8 There are number of parameters, both well established and new mathematically derived, Source of Funding: This study was partially supported by the grants of the Ministry of Education and Science of the Repub- lic of Serbia (Grants Nos. III 41022 and ON 175086). The work is original and neither the article nor part of the article was submitted elsewhere prior to this submission. Conflict of interest: nothing to declare Address for correspondence and reprint requests: Marko Banovic, M.D., Ph.D., 27 marta 26, 1000 Belgrade, Serbia. Fax: +381 11 362 9055; E-mail: markobanovic71@gmail.com 428 © 2013, Wiley Periodicals, Inc. DOI: 10.1111/echo.12404 Echocardiography