Multicenter Evaluation of Myocardial Flow Reserve as a Prognostic Marker for Mortality in ¹³ N-Ammonia PET Myocardial Perfusion Imaging

BACKGROUND: Myocardial flow reserve (MFR), measured by positron emission tomography (PET) myocardial perfusion imaging, provides valuable information on epicardial coronary disease, diffuse atherosclerosis, and microvascular function. Despite its routine use, the prognostic efficacy of 13 N-ammonia PET MFR remains unconfirmed in larger multicenter cohorts of patients with suspected or known coronary artery disease. METHODS: We considered patients from 5 sites in the REFINE PET (Registry of Flow and Perfusion Imaging for Artificial Intelligence with PET) registry who underwent 13 N-ammonia PET myocardial perfusion imaging for coronary artery disease. Clinical and imaging data were collected at the time of myocardial perfusion imaging. MFR was quantified as the ratio of stress to rest myocardial blood flow, using QPET software (Cedars-Sinai Medical Center, Los Angeles, CA). The primary outcome was all-cause mortality. Survival analyses were performed using Kaplan-Meier and Cox regression models adjusted for clinical and imaging covariates. RESULTS: In total, 6277 patients were included (median age of 65 years, 56% male). Median follow-up time was 3.8 years. There were 1895 patients with MFR ≤2 and 4382 with MFR >2. Patients with MFR ≤2 had significantly higher mortality than those with MFR >2 (n=701 [37.0%] versus n=537 [12.3%], respectively; P <0.001). Annualized all-cause mortality rates by MFR and summed stress score ranged from 1.7 to 15.8. In multivariable analysis, MFR ≤2 was independently associated with increased all-cause mortality in the overall population (hazard ratio, 2.70 [95% CI, 2.41–3.03]; P <0.001), even among patients with no perfusion defects (hazard ratio, 2.36 [95% CI, 1.93–2.89]; P <0.001). Mortality risk decreased across increasing MFR deciles, ranging from hazard ratio, 2.73 (95% CI, 2.39–3.11) to hazard ratio, 0.35 (95% CI, 0.25–0.49). CONCLUSIONS: In this large multicenter cohort, MFR derived from 13 N-ammonia PET myocardial perfusion imaging is a strong, independent predictor of all-cause mortality, even in patients with normal perfusion. An MFR of ≤2 identifies elevated risk, while higher values are associated with improved survival. These findings support the routine integration of MFR to enhance risk stratification in patients with suspected or known coronary artery disease.