The Natural History of Coronary Atherosclerosis Within the Concept of the Glagovian Arterial Remodeling in REAL-world Stable Chest Pain Population Who Underwent nonInvasive compuTed tomographY Angiography in Comparison With Invasive Quantitative Coronary Angiography and Multimodality Imaging Handled by the Advanced Post-processing Software: Clinical potentIal and Safety

Invasive coronary angiography with fractional flow reserve (FFR) is considered as the reference standard of daily clinical practice. This invasive approach is associated with potentially life-threatening complications, high expenditures, relatively high radiation exposure, and some patient discomfort. Noninvasive cardiac computed tomography angiography (CCTA) becomes a robust alternative to the invasive approach, especially when supported by other functional and anatomical noninvasive imaging modalities such as cardiac magnetic resonance (CMR), single-photon emission computed tomography (SPECT), and echocardiography (Echo). Notwithstanding, their invasive counterpart, particularly a multimodal intravascular imaging (including fractional flow reserve/ FFR, quantitative flow reserve/ QFR, optical coherence tomography/ OCT, intravascular ultrasound/ IVUS, VH-IVUS) is able to rule out the high-risk, vulnerable and obstructive atherosclerosis dramatically optimizing clinical outcomes. The clinical value of these techniques remains questionable, especially if compared between noninvasive and invasive imaging methods.

The modern-day imaging modalities allow clinical cardiology to study the natural history of atherosclerosis that can predict certain clinical outcomes paving the way for a reduction of cardiovascular mortality. The retrospective studies have shown that most atherosclerotic plaques responsible for future acute coronary syndromes are angiographically mild, and the lesion-related risk factors for major adverse cardiovascular events (MACE) are poorly understood. Pathological studies have shown that thrombotic coronary occlusion after rupture of a lipid-rich atheroma with only a thin fibrous layer of intimal tissue covering the necrotic core (a thin-cap fibroatheroma) is the most common cause of myocardial infarction and death from cardiac causes. However, the prospective identification of thin-cap fibroatheromas has not been achieved, in part because the imaging tools to identify them in vivo did not exist until recently (Stone GW, et al, 2011; DOI: 10.1056/NEJMoa1002358). Both CCTA and quantitative coronary angiography (QCA) provide us with the potential of the advanced imaging of atherosclerotic lesions, but accuracy and safety remain the keystone limitations of these approaches. CCTA has the unique advantage over detecting non-calcifying plaques in addition to calcifying lesions, thus allowing for direct visualization of early atherosclerosis stages such as lipid and fibrous atheroma, which are risk factors for future coronary events. Long-term studies report an increased risk of the adverse outcomes associated with vulnerable fibroatheroma, whereas calcifying lesions tend to remain rather stable. Studies investigating the accuracy, outcome, and, thus, the diagnostic benefit of coronary CCTA in chest pain patients are scarce (Plank F, et al, 2014; doi:10.1136/openhrt-2014-000096). The accuracy of some advanced imaging modalities has recently developed to overcome existing limitations, however, the accuracy and precision of those measurements in the different stage lesions have not been established (Kan J, et al, 2014).

In a prospective international multicenter observational study, 1080 stable chest pain patients (REALITY Advanced registry of CCTA patients) with the suspected chronic coronary syndrome will be enrolled. All of them will undergo computed tomography angiography, CMR, and/ or SPECT, and Echo. One of the cohorts will be examined with multimodality invasive imaging including quantitative coronary angiography with or without further percutaneous coronary intervention, FFR, QFR, OCT, and some of them - with IVUS, VH-IVUS. The plaque size and relevant stenosis, a composition of the atherosclerotic lesion, major adverse cardiovascular events (all-cause death, death from cardiac causes, myocardial infarction, or rehospitalization due to unstable or progressive angina, ischemia-driven revascularization) will be judged to be related to either originally treated (culprit) lesions or untreated (non-culprit) lesions. Moreover, the clinical potential of both non-invasive and invasive imaging, as well as anatomical vs functional modalities in two real-world patient flows, will be estimated with the special focus on the natural progression of atherosclerosis, clinical outcomes, and safety (contrast-induced nephropathy, radiocontrast-induced thyroid dysfunction, and radiation dose). The diagnostic accuracy will be analyzed.

The follow-up period will achieve 12 months prospectively with collected clinical events and imaging outcomes which will be determined at the baseline and 12-month follow-up.

The independent ethics expertise will be provided by the Ural State Medical University (Yekaterinburg, Russia) and Central Clinical Hospital of the Russian Academy of Sciences (Moscow, Russia). The monitoring of the clinical data with imaging as well as further CoreLab expertise (expert-level post-processing multimodal imaging software of Medis Imaging B.V., Leiden, The Netherlands) will be provided by De Haar Research Task Force, Amsterdam-Rotterdam, the Netherlands.