Cardiovascular diseases remain the leading cause of death worldwide, with coronary artery disease accounting for nearly two-thirds of cardiovascular-related deaths (1). In recent years, there has been a trend of younger onset of coronary artery disease. Premature Coronary Artery Disease (PCAD), characterized by its distinct pathological features and poor prognosis, has gradually become a focus of clinical research. PCAD is defined as coronary artery disease occurring in relatively younger populations, typically referring to cases developing before age 55 in males and 65 in females, as commonly used in major guidelines and epidemiological studies (2, 3). Studies indicate that PCAD patients frequently present with risk factors such as metabolic syndrome and smoking, and their plaques may exhibit significantly higher vulnerability compared to typical CAD patients. However, the precise pathological mechanisms remain incompletely understood. Optical Coherence Tomography (OCT), with its ultra-high resolution of 10–15 μm, enables precise identification of microscopic plaque characteristics including fibrous cap thickness, lipid core distribution, macrophage infiltration, and microchannels, earning it the designation of “optical biopsy” (4). Multiple studies have confirmed OCT's significant value in identifying vulnerable plaques, guiding interventional therapy, and predicting cardiovascular events (5, 6). Nevertheless, current research on OCT characteristics of coronary plaques in PCAD patients remains scarce, and the relationship between plaque morphology and clinical outcomes remains unclear.

This study aims to systematically analyze coronary plaque characteristics in PCAD patients using OCT technology and investigate their correlations with metabolic risk factors and major adverse cardiovascular events (MACE). The findings are expected to provide imaging-based evidence for early risk stratification, precise intervention, and prognostic evaluation in PCAD patients, thereby reducing the incidence of acute cardiovascular events.

Previous studies have established that PCAD is associated with aggressive plaque phenotypes and poor outcomes. However, detailed OCT-based characterization of plaque vulnerability in this population remains limited. Our study provides a comprehensive analysis of OCT-derived high-risk features in PCAD patients and demonstrates their strong association with metabolic risk factors and 12-month MACE. Furthermore, we identify specific OCT predictors of events, supporting the use of intravascular imaging for risk stratification in young patients.

Coronary artery disease (CAD), the leading cause of cardiovascular mortality worldwide, has shown a rising trend of earlier onset. Premature coronary artery disease (PCAD), characterized by its distinct pathological features and poor prognosis, has become a key focus of clinical research. This study systematically analyzed coronary plaque characteristics in PCAD patients using optical coherence tomography (OCT), revealing significant associations with metabolic risk factors and major adverse cardiovascular events (MACE). MACE in this study was strictly defined as cardiovascular-specific endpoints to more precisely reflect the relationship between plaque vulnerability and acute cardiovascular events. The lack of significant intergroup differences in all-cause mortality (a secondary endpoint) suggests that the high-risk profile of PCAD patients is primarily concentrated in cardiovascular-specific events.

Fibrous cap thickness (FCT) is a critical determinant of plaque stability. In this study, the PCAD group exhibited significantly lower mean FCT and a higher proportion of thin-cap fibroatheroma (TCFA) compared to controls. We used the <65 μm cutoff for TCFA definition as it remains the most widely validated and consensus-recommended value for identifying plaques at the highest risk of rupture, irrespective of patient age (8). This threshold is prognostically significant, as plaques with FCT <65 μm are associated with a substantially increased risk of future MACE. While the mean FCT in our PCAD group was higher (150.16 ± 82.71 μm), the critical finding is the significantly higher prevalence of TCFA (FCT <65 μm) in PCAD patients compared to controls (13.38% vs. 2.43%). This indicates that although the average cap may be thicker, a subset of PCAD patients harbor these very high-risk, rupture-prone lesions. This dichotomy underscores the value of OCT in identifying this high-risk subset within a broader population that may otherwise appear similar based on age or traditional risk factors alone.Thin fibrous caps are prone to shear stress, leading to lipid core exposure and subsequent platelet aggregation and thrombosis. Recent studies have further elucidated the interplay between FCT and the local inflammatory microenvironment: macrophages degrade collagen fibers via matrix metalloproteinases (MMP-2, MMP-9), while oxidized low-density lipoprotein (ox-LDL) activates the NLRP3 inflammasome, promoting IL-1β release and establishing a “inflammation-fibrous cap degradation” positive feedback loop (9). A 2023 OCT-based longitudinal study reported that patients with baseline FCT <65 µm had a nearly fourfold increased risk of plaque rupture within one year, with a post-rupture MACE rate as high as 32% (10). These findings underscore the importance of dynamic FCT monitoring and provide a rationale for intensive lipid-lowering therapy.

Our results show that PCAD patients exhibit more vulnerable plaque features—thinner fibrous caps, larger lipid arcs, and higher rates of macrophage infiltration and thrombosis—than age-matched controls. These findings are consistent with, yet more pronounced than, those reported in the CLIMA study (11) which identified FCT <75 μm, lipid arc >180°, MLA <3.5 mm², and macrophage infiltration as predictors of cardiac events in an older cohort. Notably, our PCAD group demonstrated a higher prevalence of individual high-risk features, underscoring a more aggressive plaque phenotype likely driven by metabolic and inflammatory factors prevalent in younger patients. Together, these findings highlight the utility of OCT in risk stratification across age groups and support its role in guiding early intervention in high-risk PCAD patients.

This study also found a significantly higher incidence of plaque erosion in the PCAD group, often accompanied by thrombus formation. Unlike plaque rupture, erosion is characterized by endothelial denudation with mural thrombus and is more common in younger patients and women. Emerging evidence suggests that plaque erosion may be linked to endothelial dysfunction and vasospasm, driven by reduced nitric oxide (NO) bioavailability and elevated endothelin-1 (ET-1) levels (12). The EROSION III study demonstrated that OCT-guided reperfusion strategies safely reduced stent implantation rates by 15%, with 86% of erosion cases and 41% of rupture cases avoiding stenting (13). Macrophage infiltration, a hallmark of inflammation, further influences plaque stability through phenotypic polarization (pro-inflammatory M1 vs. anti-inflammatory M2). Single-cell sequencing recently revealed that M1 macrophages account for 72% of plaque macrophages in PCAD patients—significantly higher than in older patients—and correlate positively with MMP-9 and TNF-α expression (14). M1 macrophages exacerbate oxidative stress via pro-inflammatory cytokines, while M2 macrophages promote tissue repair. Additionally, intraplaque microchannels, imaging markers of neovascularization, are closely associated with lipid core expansion and intraplaque hemorrhage. Studies report that microchannel density >5 mm² increases intraplaque hemorrhage risk by 3.5-fold and accelerates progression to complex lesions (e.g., rupture or calcified nodules) (15). Such plaques exhibit higher vulnerability, with increased risks of intimal tearing, rupture, TCFA formation, macrophage clustering, and luminal thrombosis, alongside elevated slow-flow rates post-stenting (16). These findings position microchannels as biomarkers for plaque progression and potential targets for anti-angiogenic therapies. Thrombus, a direct manifestation of acute thrombosis, may obstruct the lumen or induce distal embolism, leading to myocardial infarction or stroke. Its predictive value in this study aligns with prior research, reinforcing the importance of antithrombotic therapy in high-risk plaque management.

The PCAD group exhibited significantly higher rates of hypertension, smoking, diabetes, and dyslipidemia, highlighting metabolic dysregulation and adverse lifestyles as key drivers of plaque vulnerability. Chronic hypertension increases vascular shear stress, impairing endothelial function and promoting LDL infiltration into the subintima, where oxidation activates monocyte-to-macrophage differentiation and foam cell formation (17, 18). In this study, stenosis severity correlated positively with hypertension prevalence. Previous studies further demonstrated that intensive blood pressure lowering significantly reduces plaque lipid content, increases FCT, and decreases macrophage density (19, 20), supporting its role in delaying plaque progression. Elevated total cholesterol (TC) and LDL-C levels directly correlate with lipid arc enlargement. Lipid core expansion not only increases plaque volume but also amplifies local inflammation via pro-inflammatory cytokine release. PCSK9 inhibitors have been shown to reduce plaque lipid volume and macrophage density after 12 months of treatment (21, 22). Novel triglyceride (TG)-targeted therapies, such as APOC3 inhibitors, simultaneously lower TG and suppress microchannel formation (23), offering new avenues for personalized lipid management.

Smoking induces reactive oxygen species (ROS) generation, accelerating endothelial apoptosis and collagen degradation while upregulating MMPs to destabilize fibrous caps. In this study, smoking rates were significantly higher in the PCAD group. Persistent smoking attenuates statin-induced plaque stabilization and increases TCFA incidence, emphasizing smoking cessation as critical for long-term prognosis post-PCI in ACS patients (24). Diabetes drives macrophage polarization toward the pro-inflammatory M1 phenotype via insulin resistance (25). Recent studies show that hyperglycemia activates DNA methyltransferases (DNMTs), inducing hypermethylation of anti-inflammatory gene promoters (e.g., KLF4) and perpetuating inflammation (26), suggesting that glycemic control may modulate plaque phenotypes through epigenetic mechanisms.

This study has several limitations. First, the single-center design may limit the generalizability of our findings, although the use of standardized OCT imaging and analysis protocols strengthens internal validity. Second, the follow-up duration was limited to 12 months, which may not capture long-term cardiovascular outcomes or delayed plaque progression. Third, our predictive model for MACE lacks external validation in an independent cohort, which is necessary to confirm its broader applicability. Future multicenter studies with extended follow-up, detailed treatment adherence monitoring, and external validation are warranted to reinforce our conclusions.

In conclusion, PCAD patients exhibit distinct coronary plaque vulnerabilities strongly linked to metabolic and lifestyle risk factors. OCT enables precise identification of high-risk features (e.g., thin caps, macrophage infiltration, microchannels), providing critical imaging evidence for early risk stratification and personalized intervention. Integrating artificial intelligence, multimodal imaging, and novel targeted therapies may advance comprehensive management from “plaque diagnosis” to “precision intervention”, ultimately reducing acute cardiovascular events.