Predicting Plaque Growth Using Blood Flow Stress Markers: A Proof-of-Concept Study

Coronary artery disease (CAD) is caused by the build-up of atherosclerotic plaques within the coronary arteries. While some plaques remain stable, others continue to grow and may develop features associated with an increased risk of rupture, potentially leading to acute coronary events. Identifying plaques that are likely to progress remains a major challenge in cardiovascular medicine and could enable more personalized prevention and treatment strategies.

Wall shear stress (WSS), the frictional force generated by flowing blood on the vessel wall, plays an important role in vascular biology and atherosclerosis. Previous imaging studies using computational fluid dynamics (CFD) have demonstrated that regions exposed to low WSS are more likely to undergo plaque progression and adverse vascular remodelling. However, low WSS alone has limited predictive accuracy because many plaques exposed to low WSS do not progress over time. This suggests that additional biological factors influence how individual patients respond to adverse flow conditions.

Experimental studies have demonstrated substantial variation between individuals in endothelial cell responses to WSS. Endothelial cells line the inner surface of blood vessels and are key regulators of vascular health. These findings support the hypothesis that plaque progression is influenced not only by local haemodynamic conditions but also by patient-specific biological sensitivity to WSS. The POSSEM (Plaque Prediction Obtained with Shear Stress Endothelial Metrics) study aims to evaluate whether combining local WSS measurements with patient-specific endothelial responses improves prediction of plaque progression compared with assessment of WSS alone.

POSSEM is a prospective, longitudinal interventional study enrolling patients with established CAD who are undergoing coronary revascularisation. Baseline photon-counting computed tomography coronary angiography (PCCTA), performed as part of routine clinical care, will be used to reconstruct patient-specific coronary artery anatomy. Computational fluid dynamics will then be applied to these anatomical models to characterize local haemodynamic parameters, including WSS, within coronary plaques.

A peripheral blood sample will be collected from each participant. Endothelial colony-forming cells will be isolated and cultured to provide a patient-specific assessment of endothelial responsiveness to WSS. In laboratory experiments, these cells will be exposed to flow conditions and analysed for molecular markers associated with endothelial activation, inflammation, and cellular stress responses. These analyses will be used to quantify each participant's biological sensitivity to WSS.

Participants will undergo repeat PCCTA imaging approximately 12 months after the baseline assessment, hence, interventional study. Changes in plaque burden and plaque characteristics between baseline and follow-up scans will be evaluated and related to both local WSS measurements and endothelial responsiveness. The study will investigate whether plaques located in regions of low WSS are more likely to progress in patients demonstrating heightened biological responses to WSS compared with those exhibiting lower responsiveness.

Coronary CT datasets will undergo detailed plaque characterization and three-dimensional vessel reconstruction. CFD modelling will be used to estimate local blood flow patterns and WSS throughout the coronary tree. Plaque morphology and composition will be assessed at baseline and follow-up, enabling assessment of disease progression over time. Endothelial cell studies will be performed using standardized laboratory methods to measure flow-responsive biological pathways.

The study is intended as a proof-of-principle investigation of a combined haemodynamic and biological approach to risk prediction. The use of cultured endothelial cells is a research tool designed to establish whether individual responses to WSS contribute to plaque progression. Although this approach is not expected to be used routinely in clinical practice, the findings may support the future development of simpler blood-based biomarkers capable of identifying patients with heightened sensitivity to adverse flow conditions.

Study participation involves collection of a peripheral blood sample and an additional follow-up PCCTA scan. The repeat PCCTA exposes participants to a small additional dose of ionising radiation and requires administration of iodinated contrast material. Appropriate measures will be taken to minimise these risks, including exclusion of individuals with significant renal impairment or known contrast allergy and the use of standard dose-optimised imaging protocols.

This study seeks to improve understanding of the interaction between coronary blood flow and patient-specific vascular biology in atherosclerosis. By integrating haemodynamic and biological information, the study aims to establish whether a combined WSS-biological signature can improve prediction of coronary plaque progression and inform future strategies for personalized cardiovascular risk assessment.

• PCCTA scan (Procedure), also known as Naeotom Alpha scanner: During the scans, the patient will be cardiac monitored using ECG synchronisation. PCCTA scan acquisition and parameters will follow Barts Health's standard operating procedures and institutional protocols.
• Endothelial cell isolation from peripheral blood sample (Other): A 50mL blood sample will be collected from consenting patients. The blood will be processed to isolate peripheral mononuclear cells. These cells will be cultured to support the growth of endothelial colony forming cells (ECFCs).

Primary outcomes

• Percentage change in plaque burden over 12 months [From the first CT scan to the second CT scan- 12 months apart]: Percentage change in plaque burden over 12 months, analysed using linear regression with response to WSS as a continuous predictor
• ECFC isolation from peripheral blood sample [The process takes around 4 weeks after blood draw]: Peripheral blood will be drawn at the point of recruitment. Blood will be processed to culture endothelial colony forming cells (ECFCs).

Sex: All, ages: 40 Years to any

Inclusion Criteria:

1. Age ≥40
2. Stable angina, defined as typical symptoms with evidence of reversible ischemia in non-invasive test and/or documented obstructive coronary artery disease on coronary angiography (>70% stenosis of at least one major epicardial coronary artery or positive fractional flow reserve study)
3. Patient that is willing and can provide written informed consent.

Exclusion Criteria:

1. Acute coronary syndrome within <3 months
2. Estimated glomerular filtration rate (eGFR) <60ml/min/1.73m²
3. Previous coronary artery bypass surgery
4. Decompensated heart failure, or left ventricular ejection fraction ≤30%
5. Patient allergic to contrast or cannot receive treatment with aspirin, heparin, or thienopyridines
6. Anticipated life expectancy <2 years
7. Flow limiting coronary artery disease in the proximal segments of all the 3 epicardial coronaries
8. History of heart transplantation
9. Patient that requires surgical revascularization
10. Extensive coronary artery disease (i.e., multiple chronic total occlusions) or tortuous coronary anatomy that does not allow assessment of the coronary arteries with intravascular imaging
11. Pregnant women will be excluded. All women of childbearing potential will undergo a pregnancy risk assessment and a urine pregnancy test prior to the 12-month PCCTA scan, in line with standard clinical practice for all PCCTA scans.