This study, designed as a retrospective registry, aims to investigate the relationship and potential interplay between fractional flow reserve (FFR) or instantaneous waves free ratio (iFR) with wall shear stress (WSS) in the context of intermediate coronary stenosis.

BACKGROUND AND RATIONALE Despite great advances in atherothrombosis science, the complex interplay of factors leading to plaque progression remains elusive. Specifically, the dynamics leading a stable plaque towards rupture and over imposed thrombosis are largely speculative. Wall shear stress (WSS), the mechanical force elicited by blood flow on the vessel walls, is emerging as a potent trigger of bio-humoral processes eventually leading to endothelial damage, plaque progression and destabilization.

Fractional flow reserve (FFR), assessing the aggregate hemodynamical significance of a stenosis on the subtended myocardium, stratifies the risk of major adverse cardiovascular events and reduces their occurrence when used to guide revascularization. While this event reduction is mainly driven by ischemia-caused urgent revascularization, it is emerging that FFR-guided revascularization may also reduce myocardial infarction.

While the physiological relationship between a lesion's FFR and resulting ischemia in the subtended myocardium is intuitive, the mechanisms linking FFR to atherothrombosis are less clearly defined.

Lesions with lower FFR are associated with adverse atherosclerotic plaque characteristics (APCs), however, the causative nexus of this relationship is not well established. It has been proposed both that the physiological base for this relation underlies in disturbed lesion hemodynamics, occurring at a greater extent as the degree of functional obstruction increases (i.e. FFR reduction drives APCs), and that APCs directly impair the vessel's vasodilatory reserve resulting in detrimental hyperemic perfusion (i.e. APCs drive FFR reduction).

WSS measures the regional tangential hemodynamic forces produced by viscous blood flow on the endothelium, which is established drivers of plaque progression and transformation toward an adverse plaque phenotype. Intriguingly, WSS may thus represent the missing link between FFR and atherothrombosis.

Few studies have focused on the interplay of FFR and WSS and the provided results are inconclusive (9, 10). This relation remains thus to be fully characterized.

This study will investigate the association of aggregate with regional hemodynamic forces as defined by the lesion-level relation of FFR or instantaneous wave-free ratio (iFR) and regional WSS across the lesion.

STUDY DESIGN This is a retrospective observational multi-center study, including consecutive patients who underwent coronary angiography at for symptom/ischemia-driven, suspected stable coronary artery disease or for acute coronary syndromes (ACS) with evidence of at least one lesion with 30-90% diameter-stenosis, that underwent subsequent iFR/FFR assessment.

Coronary angiography of the screened patients will be retrospectively evaluated by an experienced Interventional cardiologist and, if deemed suitable for baseline angiographic reconstruction will be included in this registry.

3-dimensional (3D) geometric reconstructions of each patient's target vessel will be created by using end-diastolic angiographic projections at least 25° apart. Computational fluid dynamics models will be applied to derive regional WSS values across the stenosis.

Clinical baseline characteristics and angiographic features obtained by visual and functional assessment, and 3-D reconstruction and computation, along with major adverse cardiovascular events, will be collected in a dedicated electronic form.

The analysts performing angiographic 3-D reconstruction and WSS computations will be blinded to FFR/iFR values and clinical data.

STUDY ENDPOINTS This study will investigate the association of aggregate and regional hemodynamic forces as established by the lesion-level relation of FFR/iFR with regional WSS across the lesion.

The association of regional WSS with major cardiovascular adverse events at available follow-up will be further evaluated to assess if lesion-level WSS might predict overall patient-level outcomes (in case of more than one lesion for a single patient, the lesion with the highest WSS will be considered for this analysis).

Inclusion Criteria:

• Angiography performed for suspected symptom/ischemia-driven stable coronary artery disease or for acute coronary syndromes
• At least one lesion with 30-90% diameter stenosis at invasive angiography with FFR/iFR assessed (for patients with acute coronary syndromes, the invasive assessment will be performed on non-culprit stenosis
• Patient informed consent for data collection and publication in anonymous studies

Exclusion Criteria:

• Quality of angiographic frames not sufficient for 3D-reconstruction and/or computations
• Patients denying informed consent

- The study will include any patient referred for coronary angiography at each involved center and with a subsequent invasive physiological assessment performed with FFR or iFR (or both) at operating physician's discretion on intermediate coronary stenosis (diameter of stenosis ranging from 30-90% at visual angiographic estimation).