Prevalence, Predictors, and Outcomes of Impaired Myocardial Flow Reserve Among Symptomatic Patients with a Coronary Artery Calcium Score of 0

Coronary artery calcium (CAC) scoring has been incorporated into preventive guidelines and is increasingly studied as a gatekeeper to further testing. A CAC score of 0 is traditionally associated with low cardiovascular risk. However, the CAC score primarily quantifies calcified plaque, potentially overlooking noncalcified atherosclerosis and microvascular dysfunction, which also contribute to adverse outcomes. This study aimed to assess the prevalence, predictors, and prognostic value of impaired PET-derived myocardial flow reserve (MFR) in patients with a CAC score of 0. <b>Methods:</b> We analyzed 2,270 symptomatic patients across 2 centers who had a CAC score of 0 and underwent a clinically indicated PET. Multivariate logistic regression was used to identify predictors of impaired MFR. Nested Cox models were used to assess the incremental prognostic value of MFR for a composite of all-cause death, myocardial infarction/late revascularization, and heart failure admission. The C-index and net reclassification improvement (NRI) were also calculated. <b>Results:</b> The prevalence of impaired MFR was 30.5%. Significant predictors included age, morbid obesity (BMI ≥ 40 kg/m²), diabetes, hypertension, and chronic kidney disease. Over a median follow-up of 1.63 y, impaired MFR was associated with higher event rates (hazard ratio, 4.69; 95% CI, 2.69-8.2). Adding MFR improved risk prediction (C-index, 0.784-0.815; <i>P</i> < 0.001; categoric NRI, 0.163; continuous NRI, 0.899). The impact of MFR was most pronounced in the intermediate risk category, upgrading 16.8% of patients (4% annual event rate) and downgrading 53.9% (0.9% annual event rate). <b>Conclusion:</b> One in 3 symptomatic patients with a CAC score of 0 had impaired MFR, which was independently associated with adverse outcomes. MFR enhanced risk stratification, highlighting its utility in identifying high-risk individuals with a CAC score of 0 who may benefit from intensive therapy.