Cumulative Incidence and Distribution of Coronary Lesions with Vulnerable Characteristics in Patients with Stable Angina Pectoris: Insights from Intravascular Ultrasound and Coronary Angiography – Implications for Plaque Vulnerability and Modern Multimodality Imaging

Abstract: Objective: Although vulnerable plaques are well-recognized precursors of acute coronary syndromes (ACS), their prevalence and potential cumulative nature in patients with clinically stable angina pectoris (SAP) were poorly understood in the early 2000s. Prior pathological and angiographic studies suggested multiple complex plaques in unstable presentations, but data in stable disease were limited. This study aimed to determine the prevalence of coronary plaques exhibiting vulnerable features — defined as positive arterial remodeling on intravascular ultrasound (IVUS) and complex morphology on angiography — in patients with SAP, and to investigate whether such lesions exhibit a cumulative pattern (i.e., the presence of one vulnerable lesion predicts additional ones elsewhere). Methods: This prospective observational study enrolled consecutive patients with SAP undergoing coronary angiography and IVUS evaluation. Vulnerable plaque characteristics were defined as: (1) positive remodeling (remodeling index >1.0, indicating outward vessel expansion) on grayscale IVUS, and (2) complex plaque appearance on angiography (e.g., irregular borders, ulceration, thrombus, or haziness). Target lesions (≥30% angiographic stenosis) were classified as complex or smooth. IVUS was performed to assess remodeling and plaque distribution across multiple coronary segments. Associations between positive remodeling, complex morphology, and multiplicity of lesions were analyzed using odds ratios (OR) with 95% confidence intervals (CI). Results: Sixty-seven target lesions were evaluated in the cohort. Positive remodeling was identified in 30 lesions (44.8%), while complex angiographic appearance was present in 16 lesions (23.9%). Notably, multiple complex plaques were observed in 21 patients (31.3%). Plaques with positive remodeling were significantly more likely to exhibit complex angiographic features (12/30 vs. 4/37; p=0.005) and to coexist with complex plaques at remote sites (35/30 vs. 23/37; p=0.04). The presence of positive remodeling strongly predicted the occurrence of multiple complex lesions elsewhere (OR 5.6; 95% CI 1.7–18.3), supporting a cumulative incidence pattern of vulnerable characteristics. Conclusions: This study demonstrated that multiple coronary plaques with vulnerable features (positive remodeling on IVUS and complex morphology on angiography) are present in nearly one third (≈31%) of patients with stable angina pectoris. The findings suggest a cumulative character to vulnerable lesion development, where the identification of one such plaque increases the likelihood of additional vulnerable sites. These early observations using combined IVUS and angiography provided foundational evidence that subclinical vulnerable plaque burden extends beyond symptomatic lesions even in stable disease. Subsequent advancements, including virtual histology IVUS (VH-IVUS), near-infrared spectroscopy (NIRS), and optical coherence tomography (OCT), have confirmed and refined these insights: studies like PROSPECT, VIVA, and ATHEROREMO-IVUS (2008–2018) showed higher frequencies of thin-cap fibroatheroma (TCFA), large necrotic cores, and plaque rupture in non-culprit segments of ACS patients compared to SAP, with multiplicity of high-risk features predicting major adverse cardiac events (MACE) over long-term follow-up. By 2026, current guidelines (e.g., 2019 ESC chronic coronary syndromes and 2023 updates) incorporate intracoronary imaging for risk stratification in selected high-risk stable patients, emphasizing secondary prevention (intensive lipid-lowering, anti-inflammatory therapies) when multiple vulnerable plaques are detected. Multimodality imaging (e.g., OCT-IVUS hybrids) now enables precise quantification of cap thickness (<65 µm for high vulnerability) and lipid burden, supporting personalized approaches to stabilize plaques and prevent progression to ACS. Keywords: Stable angina pectoris, vulnerable plaque, positive remodeling, complex coronary lesion, intravascular ultrasound (IVUS), coronary angiography, cumulative incidence, thin-cap fibroatheroma, plaque multiplicity, acute coronary syndrome risk.