Background Impaired vasodilator function is an early manifestation of coronary artery disease and may precede angiographic stenosis. It is unknown whether non-invasive assessment of coronary vasodilator function in patients with suspected or known coronary artery disease (CAD) carries incremental prognostic significance. Methods and Results 2783 consecutive patients referred for rest/stress PET were followed for a median of 1.4 years (inter-quartile range: 0.7–3.2 years). The extent and severity of perfusion abnormalities were quantified by visual evaluation of myocardial perfusion images (MPI). Rest and stress myocardial blood flow (MBF) were calculated using factor analysis and a 2-compartment kinetic model, and were used to compute coronary flow reserve (CFR=stress/rest MBF). The primary endpoint was cardiac death. Overall 3-year cardiac mortality was 8.0%. The lowest tertile of CFR (<1.5) was associated with a 5.6-fold increase in the risk of cardiac death (95%CI 2.5–12.4, p<0.0001) compared to the highest tertile. Incorporation of CFR into cardiac death risk assessment models resulted in an increase in the c-index from 0.82 (95%CI 0.78–0.86) to 0.84 (95%CI 0.80–0.87, p=0.02) and in a net reclassification improvement (NRI) of 0.098 (95%CI 0.025–0.180). Addition of CFR resulted in correct reclassification of 34.8% of intermediate risk patients (NRI=0.487, 95%CI 0.262–0.731). Corresponding improvements in risk assessment for mortality from any cause were also demonstrated. Conclusions Non-invasive quantitative assessment of coronary vasodilator function using PET is a powerful, independent predictor of cardiac mortality in patients with known or suspected CAD and provides meaningful incremental risk stratification over clinical and gated MPI variables.

Objectives We sought to relate imaging findings on PET to adverse cardiac events in patients referred for evaluation of known or suspected cardiac sarcoidosis (CS). Background Although cardiac positron emission tomography (PET) is commonly used to evaluate patients with suspected CS, the relationship between PET findings and clinical outcomes has not been reported. Methods We studied 118 consecutive patients with no history of CAD who were referred for PET using 18F-fluorodeoxyglucose (FDG) [to assess for inflammation] and 82Rubidium [to evaluate for perfusion defects (PD)] following a high fat / low carbohydrate diet to suppress normal myocardial glucose uptake. Blind reads of the PET data categorized cardiac findings as (a) normal; (b) positive PD or FDG; (c) positive PD and FDG. Images were also used to identify if findings for extra cardiac sarcoidosis were present. Adverse events (AE) -- death or sustained ventricular tachycardia (VT) -- were ascertained by electronic medical records, defibrillator interrogation, patient questionnaires and phone interviews. Results Among the 118 patients (age 52±11; males 57%, mean ejection fraction 47%±16%), 47 (40%) had normal and 71 (60%) abnormal cardiac PET findings. Over a median follow-up of 1.5 years, there were 31 (26%) adverse events (27 VT and 8 deaths). Cardiac PET findings were predictive of AE with the presence of both a PD and abnormal FDG (29% of patients) being associated with hazard ratio of 3.9 (p<0.01) and remaining significant after adjusting for left ventricular ejection fraction (LVEF) and clinical criteria. Extra-cardiac FDG uptake (26% of patients) was not associated with AE. Conclusions The presence of focal PD and FDG uptake on cardiac PET identifies patients at higher risk of death or VT. These findings offer prognostic value beyond Japanese clinical criteria, the presence of extra cardiac sarcoidosis and LVEF.

Background Coronary microvascular dysfunction (CMD) is a prevalent and prognostically important finding in patients with symptoms suggestive of coronary artery disease (CAD). The relative extent to which CMD affects both genders is largely unknown. Methods and Results We investigated 405 men and 813 women referred for evaluation of suspected CAD with no previous history of CAD and no visual evidence of CAD on rest/stress positron emission tomography (PET) myocardial perfusion imaging. Coronary flow reserve (CFR) was quantified and CFR<2.0 used to define the presence of CMD. Major adverse cardiac events (MACE), including cardiac death, non-fatal myocardial infarction, late revascularization and hospitalization for heart failure, were assessed in blinded fashion over a median follow-up of 1.3 years (IQR 0.5–2.3 years). CMD was highly prevalent both in men and women (51% and 54%, respectively; P(Fisher exact test)=0.39; P(equivalence)=0.0002). Regardless of gender, CFR was a powerful incremental predictor of MACE (hazard ratio 0.80 [95% CI 0.75–086] per 10% increase in CFR; P<0.0001) and resulted in favorable net reclassification improvement (NRI=0.280 [95% CI 0.049–0.512]), after adjustment for clinical risk and ventricular function. In a subgroup (N=404; 307 female/97 male) without evidence of coronary artery calcification (CAC) on gated CT imaging, CMD was common in both genders, despite normal stress perfusion imaging and zero CAC (44% of men versus 48% of women; P(Fisher exact test)=0.56; P(equivalence)=0.041). Conclusions CMD is highly prevalent among at risk individuals and is associated with adverse outcomes regardless of gender. The high prevalence of CMD in both genders suggests that it may be a useful target for future therapeutic interventions.

In symptomatic patients without overt CAD, impaired CFR was independently associated with diastolic dysfunction and adverse events, especially HFpEF hospitalization. The presence of both coronary microvascular and diastolic dysfunctions was associated with a markedly increased risk of HFpEF events.