<p>Fractional flow reserve (FFR) is the clinical gold standard for assessing the functional severity of coronary artery stenosis. Invasive FFR measurements require the use of a pressure guide wire, which may alter coronary hemodynamics relative to the wire-free state. Yet most computational FFR models neglect the guide wire in the computations, potentially introducing a bias relative to clinical measurements. In this study, we used an image-based geometrically multi-scale computational fluid dynamics (CFD) model to systematically quantify the impact of pressure guide wires on FFR and coronary flow reserve (CFR) across varying stenosis severities, lesion configurations, and anatomical locations. Key novelties of this work include: i) assessment of the role of distal microvascular resistance in modulating FFR measurements, and ii) assessment of guide wire effects on CFR, including comparison with classical experimental data. Our findings demonstrate that the pressure guide wire consistently reduces FFR values, with the effect becoming more pronounced in severe, serial, and diffuse subtypes of stenoses. In addition, larger microvascular resistance attenuates the sensitivity of FFR to guide wire effects. These findings highlight the clinical significance of guide wire effects and emphasize the need to account for them in non-invasive FFR frameworks, thereby improving the accuracy and reliability of CFD-based physiological assessments.</p>