Robust estimation of the 18F-flurpiridaz retention fraction for quantification of myocardial blood flow in CAD patients

Objectives: 18F-flurpiridaz (FPZ) is a new PET perfusion tracer with close to 100% extraction fraction during the first-pass transit through the coronary circulation. High tracer extraction is ideal for accurate quantification of myocardial blood flow (MBF) but requires compartment modeling with dynamic PET imaging. Early washout during the first few minutes following tracer extraction, results in reduced retention and image contrast in the standard perfusion images. MBF estimation using these images with a net retention (microsphere) model is computationally simpler, but requires a-priori knowledge of the retention fraction over a wide range of MBF values. This study measured the retention fraction of FPZ in patients recruited as part of the Phase 3A trial.

Methods: N=100 subjects were identified from the ‘Phase 3 Multi-center Study to Assess PET Imaging of Flurpiridaz F 18 Injection in Patients with CAD’ trial with available dynamic images acquired at rest and during persantine or adenosine stress. Following a low-dose CT scan for attenuation correction, rest dynamic PET images were acquired for 15 min (15x10 sec, 5x30 sec, 5x60 sec, 1x300 sec) starting with injection of 2.8±0.2 mCi FPZ, and reconstructed without any apodizing- or post-filter. Hyperemia was induced using adenosine (140 ug/min/kg x 6 min) or persantine (140 ug/min/kg x 4 min) followed by stress PET dynamic imaging with the same protocol settings used at rest starting with injection of 6.1±0.2 mCi FPZ. Regional and whole-LV average myocardial blood flow (MBF) was quantified at rest and stress using a 2-tissue-compartment model including subtraction of residual rest activity for the stress analysis (4DM-PET). Standard uptake values (SUV) were measured in the LV myocardium from 5-15 min post-injection, including subtraction of residual rest activity from the stress values. For a tracer with 100% retention the SUV ratio (SUVR = SUVstress/SUVrest) provides a direct measurement of myocardial flow reserve (MFR = MBFstress/MBFrest). Therefore, the actual FPZ retention fraction was estimated simply as the ratio of SUVR/MFR values measured over the full range of stress MBF values. A modified Renkin-Crone function was fit to the ratio data and reported as the FPZ retention fraction RF = 1 - exp(-PS/MBF) where PS = B + A × MBF is related to the capillary Permeability × Surface-area product and early washout kinetics of the tracer.

Results: Rest and stress MBF values were 0.78±0.23 and 2.17±0.80 mL/min/g respectively. The corresponding SUVs were measured as 70±52 and 114±88 g/mL. The average stress/rest SUVR was significantly lower than the measured MFR (1.61±0.37 vs 2.92±1.20; p<0.0001) suggesting that FPZ retention was ~55% on average during peak stress compared to rest (Fig.2). Parameters of the Renkin-Crone retention function were estimated as PS = 2.06 − 0.03 × MBF mL/min/g. Estimated confidence intervals indicated that the slope parameter was not significantly different from zero, and a simple average value of PS = 2.0 provided equivalent fit to the data. The corresponding retention function showed very good correlation with the SUVR/MFR data (R² = 0.70) suggesting a retention fraction of 92% at rest and 60% at the mean stress MBF value.

Conclusions: FPZ demonstrates high tracer retention over a wide range of MBF consistent with high contrast myocardial perfusion imaging, and similar to previously reported values for 13N-ammonia.

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