Role of the Collateral Circulation in Stable Angina: Circulation Study Finds

A recent study concluded that coronary collateralization is associated with ischemic burden and may reduce the intensity of ischemic chest pain. The authors highlighted that this may explain the nonlinear relationship between stenosis, ischemia, and angina.

The findings are published in Circulation in December 2025

The Clinical Disconnect in Stable Angina

In patients with stable coronary artery disease, conventional clinical understanding often assumes a straightforward mechanistic construct: restricted blood flow leads to ischemia, and this oxygen supply-demand imbalance manifests as angina. Intuitively, cardiologists might expect the most severe coronary stenoses or the largest burden of ischemia to cause the most debilitating symptoms. However, clinical evidence has repeatedly demonstrated a surprisingly weak correlation between the measured extent of ischemia and the patient-reported severity or frequency of angina. This fundamental disconnect has significant clinical implications, as guidelines relying solely on physiological measures of stenosis severity, such as Fractional Flow Reserve (FFR), may fail to accurately identify which patients stand to gain the most symptomatic relief from revascularization.

Study Overview

To address this challenge, the ORBITA-STAR study was conducted as a prospective, multicenter, n-of-1, placebo-controlled trial. Fifty-one participants with angina and severe single-vessel CAD (≥70%) referred for PCI were enrolled. Antianginal medications were stopped, and daily angina frequency was recorded for 14 days using a smartphone app. The invasive protocol included baseline FFR and iFR measurements, followed by a blinded sequence of four 60-second low-pressure balloon occlusions across the stenosis, each paired randomly with an audio-visually identical placebo inflation. During each episode, the Collateral Flow Index (CFI) was calculated, and patients immediately rated their pain on a 10-point scale, allowing derivation of a placebo-controlled pain intensity score.

The Key Findings from the Study

The analysis yielded three key findings for this cohort (mean age 63±9 years, 78% men) with significant stenosis:

• First, consistent with prior literature, the daily frequency of angina reported by the patients showed little association with the severity of ischemia as measured by FFR or iFR.

• Second, and pivotally, the study provided strong evidence of an inverse adaptive relationship: lower (more ischemic) FFR and iFR values were strongly associated with greater collateral blood flow (higher CFI). This suggests that the collateral circulation adapts and recruits in response to a higher chronic ischemic burden.

• Third, and confirming the clinical relevance of this adaptation, there was strong evidence that greater collateralization (higher CFI) was associated with significantly reduced placebo-controlled pain intensity scores. Furthermore, testing for acute adaptation, the CFI and pain scores remained stable between sequential balloon occlusion episodes, showing little evidence of ischemic preconditioning during the procedure.

Clinical Importance: The Collateral Effect on Symptom Burden

For practicing physicians, these findings clarify why patients with severe coronary stenosis may report surprisingly little angina: well-developed collateral vessels can blunt ischemic pain despite physiologically significant lesions. This helps explain the long-recognized mismatch between stenosis severity, ischemia, and symptom burden. The study reinforces that angina severity alone is an unreliable indicator of ischemic burden and that collateral circulation is a powerful symptom modulator. It also suggests that the symptomatic benefit of medical therapy may, in part, reflect the time it allows for collateral maturation. Overall, predicting symptom relief after PCI must account for individual variability in collateralization, not just stenosis physiology.

Reference: Rajkumar CA, Foley MJ, Ahmed-Jushuf F, Chotai S, Simader FA, Mohsin M, Salih A, Ganesananthan S, Bual N, Petraco R, Nijjer SS. The Role of the Collateral Circulation in Stable Angina: An Invasive Placebo-Controlled Study. Circulation. 2025 Oct 27;152(22).