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Currently, cutoffs of quantitative [15O]H2O PET to detect fractional flow reserve (FFR)-defined coronary artery disease (CAD) were derived from a single cohort that included patients without prior CAD. However, prior CAD, sex, and age can influence myocardial blood flow (MBF). Therefore, the present study determined the influence of prior CAD, sex, and age on optimal cutoffs of hyperemic MBF (hMBF) and coronary flow reserve (CFR) and evaluated whether cutoff optimization enhanced diagnostic performance of quantitative [15O]H2O PET against an FFR reference standard. Methods: Patients with chronic coronary symptoms underwent [15O]H2O PET and invasive coronary angiography with FFR. Optimal cutoffs for patients with and without prior CAD and subpopulations based on sex and age were determined. Results: This multicenter study included 560 patients. Optimal cutoffs were similar for patients with (n = 186) and without prior CAD (hMBF, 2.3 vs. 2.3 mL center dot min-1 center dot g-1; CFR, 2.7 vs. 2.6). Females (n = 190) had higher hMBF cutoffs than males (2.8 vs. 2.3 mL center dot min-1 center dot g-1), whereas CFRs were comparable (2.6 vs. 2.7). However, female sex-specific hMBF cutoff implementation decreased diagnostic accuracy as compared with the cutoff of 2.3 mL center dot min-1 center dot g-1 (72% vs. 82%, P , 0.001). Patients aged more than 70 y (n = 79) had lower hMBF (1.7 mL center dot min-1 center dot g-1) and CFR (2.3) cutoffs than did patients aged 50 y or less, 51-60 y, and 61-70 y (hMBF, 2.3-2.4 mL center dot min-1 center dot g-1; CFR, 2.7). Age-specific cutoffs in patients aged more than 70 y yielded comparable accuracy to the previously established cutoffs (hMBF, 72% vs. 76%, P = 0.664; CFR, 80% vs. 75%, P = 0.289). Conclusion: Patients with and without prior CAD had similar [15O]H2O PET cutoffs for detecting FFR-defined significant CAD. Stratifying patients according to sex and age led to different optimal cutoffs; however, these values did not translate in

Background and aims: In this study, we investigated whether increased renin angiotensin aldosterone system (RAAS) activation and endothelin-1 levels are related to coronary artery calcium (CAC) score, total plaque volume (TPV), high risk plaque, hyperemic myocardial blood flow (MBF) and coronary microvascular dysfunction (CMD). Methods: In a prospective, observational, cross-sectional cohort, renin as a marker for RAAS activation and endothelin-1 were measured in peripheral venous blood of 205 patients (64% men; age 58 ± 8.7 years) with suspected coronary artery disease (CAD) who underwent coronary computed tomography angiography (CCTA), [15O]H2O positron emission tomography (PET) perfusion imaging and invasive fractional flow reserve (FFR) measurements. Patients were categorized into three groups based on FFR (≤0.80) and hyperemic MBF <2.3 ml/min/g: [1] obstructive CAD (n = 92), [2] CMD (n = 26) or [3] no or non-obstructive CAD (n = 85). Results: After correction for baseline characteristics, including RAAS inhibiting therapy, renin associated positively with CAC score and TPV, but not with hyperemic MBF (p < 0.01; p = 0.02 and p = 0.23). Patients with high risk plaque displayed higher levels of renin (mean logarithmic renin 1.25 ± 0.43 vs. 1.12 ± 0.35 pg/ml; p = 0.04), but not endothelin-1. Compared to no or non-obstructive CAD patients, renin was significantly elevated in obstructive CAD patients but not in CMD patients (mean logarithmic renin 1.06 ± 0.34 vs. 1.23 ± 0.36; p < 0.01 and 1.06 ± 0.34 vs. 1.16 ± 0.41 pg/ml; p = 0.65). Endothelin-1 did not differ between the three patient groups. Conclusions: Our report provides evidence that RAAS activity measured by renin concentration is elevated in patients with coronary atherosclerosis and high risk plaque but not in patients with CMD, whereas endothelin-1 is not related to either.