Progressive Myocardial Flow Reserve Impairment Across Cardio-Kidney-Metabolic Syndrome Stages Is Associated with Cardiovascular Risk: Insights from Cardiac PET

BackgroundCardiovascular-Kidney-Metabolic (CKM) Syndrome is a progressive multisystem construct linked to elevated cardiovascular risk. Coronary microvascular dysfunction may reflect early CKM pathophysiology, but its prevalence and prognostic relevance across CKM stages are unclear. We hypothesized that myocardial flow reserve (MFR), measured by 82Rb PET/CT, declines with advancing CKM stage and provides prognostic value across the spectrum. MethodsWe retrospectively analyzed 5,502 patients who underwent rest-stress 82Rb PET myocardial perfusion imaging between 2016 and 2022. CKM stages 0-4 were defined using a structured algorithm integrating clinical, metabolic, and imaging features. Abnormal MFR was defined as <2.0. The primary outcome was a composite of all-cause death, myocardial infarction, stroke, or heart failure hospitalization. Associations between MFR, CKM stage, and outcomes were assessed using Cox models and Kaplan-Meier curves stratified by MFR and CKM stage. ResultsMFR declined stepwise with increasing CKM stage, from 2.65 {+/-} 0.86 in Stage 0-1 to 2.08 {+/-} 0.73 in Stage 4 (p < 0.001). Abnormal MFR prevalence rose from 21% to 50%. Over a median follow-up of 3.9 years (IQR 2.4-5.6), 1,527 composite events occurred. Both abnormal MFR (HR 2.23; 95% CI: 1.96-2.53) and higher CKM stage (Stage 4 vs. Stage 0-1: HR 2.99; 95% CI: 1.71-5.21) independently predicted events. Abnormal MFR further stratified risk within each CKM stage, with the strongest association in Stage 0-1 (HR 7.26; 95% CI: 2.36-22.4; p-interaction < 0.05). ConclusionsMFR is progressively lower across CKM syndrome stages. Abnormal MFR is independently associated with cardiovascular events and provides incremental prognostic value within each CKM stage--most notably in early-stage disease--supporting its potential role in improving risk stratification across the CKM continuum.