A Prospective Natural-History Study of Coronary Atherosclerosis (PROSPECT)

The PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) trial enrolled 697 patients with acute coronary syndrome who underwent three-vessel coronary imaging by IVUS and virtual histology-IVUS at index catheterization. Patients were followed for 3.4 years for major adverse cardiovascular events (MACE).

Approximately 11.6% of MACE events at follow-up arose from non-culprit lesions that were angiographically mild at baseline (less than 70% stenosis). Thin-cap fibroatheroma (TCFA) — a plaque morphology characterized by a necrotic core with thin fibrous cap, identifiable by VH-IVUS — was the strongest predictor of future events at non-culprit sites (HR 3.35). Plaques with large plaque burden (≥70%) and small minimum lumen area (≤4.0 mm²) were also significant predictors.

PROSPECT established that coronary atherosclerosis events cannot be predicted from stenosis severity alone. More than half of patients who developed future coronary events did so from lesions that were not “significant” by angiographic criteria at baseline. The culprit plaque for an acute MI is often a modest stenosis that ruptures unpredictably — but IVUS-based morphological features (TCFA, plaque burden) identify higher-risk lesions earlier.

The implications extend to imaging strategy: angiography characterizes stenosis, but plaque morphology (characterizable by IVUS, VH-IVUS, and increasingly by CCTA with plaque characterization) identifies biologically vulnerable lesions that will rupture before they narrow the lumen substantially.

We rate the evidence strong. A prospective multi-vessel IVUS study in 697 ACS patients demonstrating that future coronary events arise predominantly from non-obstructive plaques with specific morphological vulnerability features — foundational evidence for the biological underpinning of plaque vulnerability as the key risk determinant beyond stenosis.