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).