Combining Intraplaque Neovascularization with Risk Stratification by Carotid Stress Echo (The CIRCE Study)

Stress echo (SE) is one of the most accessible tests used to select patients for angiography, but suffers from moderate sensitivity and specificity for cardiovascular (CV) outcomes. In Ontario alone, of the >100,000 SEs performed every year, 90% are normal, and patients may have little follow-up. It is estimated that 3-5% (~4,000 patients/year) of those with a negative SE have a major adverse cardiovascular event(MACE) within 3 years. We have demonstrated that adding carotid plaque assessment by ultrasound to the SE is feasible and improves testing with a net reclassification improvement (NRI) of 25% for coronary artery disease (CAD). We reported that activity of plaque adds further discriminatory power for predicting CAD and MACE. Plaques can be assessed by intraplaque neovascularization (IPN), which occurs in response to hypoxia or inflammation within the lesion. IPN occurs when vessels grow from the vasa vasorum into the lesion, resulting in a fragile and leaky network at risk of rupture and hemorrhage. IPN of carotid arterial plaque can now be quantified using ultrasound contrast. We hypothesize that addition of carotid IPN detection at the time of SE will enhance risk prediction for MACE. We plan to demonstrate that plaque inflammatory activity, detected by IPN serves as a powerful imaging biomarker of CAD and CV events to improve the sensitivity of SE.

This is a prospective, parallel, 6-centre study assessing IPN + SE in 1500 consecutive outpatients referred for SE. Patients will be recruited from a community-based cardiac clinic, and the Universities of Queen’s, Dalhousie, Calgary, Toronto, and RUMC(Chicago). The NPV and sensitivity of IPN + SE for ruling out CAD will be determined. Follow-up will be 3-year MACE. The proposal is founded upon a simple, inexpensive, and safe addition to the workflow of an existing non-invasive test. Extensive work to date indicates that plaque assessment added to SE will enhance stratification to reduce referral for unnecessary angiography and better identify patients at risk. This multi-center study of IPN + SE is expected to show increased predictive power for MACE, establishing a new standard for CV risk stratification.

The CIRCE study was the top ranked proposal in its committee and awarded the 2020/2021 CIHR Project grant led by Queen’s University.