Incremental Prognostic Value of Subendocardial Myocardial Flow Reserve in Patients With Normal Perfusion

Although the prognostic utility of positron emission tomography (PET) myocardial flow reserve (MFR) is well established, emerging data suggest that reduced subendocardial flows also predict adverse outcomes. However, the incremental value of subendocardial MFR (MFR_SE) beyond transmural MFR (MFR_TM) remains unclear.

We studied patients in a multicenter PET registry with normal perfusion on stress/rest Rb-82 PET, excluding those with a previous history of coronary artery bypass surgery, heart transplantation, or left ventricular ejection fraction <40%. The optimal MFR_SE cutoff for predicting major adverse cardiovascular events (MACEs; death, myocardial infarction [MI], revascularization, or heart failure [HF] hospitalization) was determined using Youden's index. Patients were stratified into 3 groups: concordant-normal (MFR_TM ≥2.0; MFR_SE ≥2.1), discordant (low-MFR_SE, normal MFR_TM), and abnormal MFR_TM. Clinical outcomes were compared by MFR groups.

Among 6603 patients (normal N=4103; discordant N=885; abnormal N=1615) the mean age was 66.3±12.4 years, and 54% were women. Compared with the concordant-normal group, patients with discordant low-MFR_SE were older and more likely to have hypertension, diabetes, peripheral artery disease, and previous percutaneous coronary intervention. The median MFR_TM for normal, discordant, and abnormal groups were 2.86, 2.15, and 1.72, respectively. Over a median follow-up of 4.9 years, 1661 MACE events occurred. Discordant low-MFR_SE patients had a higher risk of MACE (hazard ratio [HR], 1.41; 95% CI, 1.22-1.64) and all-cause mortality (HR, 1.36; 95% CI, 1.14-1.61) compared with concordant-normal patients. The discordant group had an intermediate absolute risk of MACE, with an adjusted annualized event rate of 5.79% (95% CI, 5.10-6.49) compared with 3.99% (95% CI, 3.67-4.30; P<0.001) in the concordant-normal group and 8.35% (95% CI, 7.71-9.00; P<0.001) in the abnormal MFR_TM group.

Subendocardial MFR reveals clinically meaningful risk heterogeneity among patients with preserved transmural flow reserve, helping refine risk stratification beyond traditional PET metrics.