Systemic atherosclerosis assessment using lipoprotein(a) and angioscopy: a prospective study of cholesterol crystal detection

Background

Non-obstructive general angioscopy (NOGA) enables direct, high-resolution visualization of the aortic intimal surface in vivo and allows real-time assessment of plaque morphology and activity. Ruptured aortic plaques (RPs) have been associated with systemic complications, including cerebral infarction, renal dysfunction, and peripheral organ injury. One proposed mechanism underlying these complications is the embolization of cholesterol crystals (CCs) released from vulnerable plaques into the systemic circulation. These CCs can trigger inflammatory responses, endothelial dysfunction, and microvascular obstruction, ultimately leading to distal organ damage.

Lipoprotein(a) [Lp(a)] has emerged as a residual cardiovascular risk factor independent of low-density lipoprotein cholesterol (LDL-C). Elevated Lp(a) levels are genetically determined and have been associated with systemic atherosclerosis, plaque progression, and thrombotic events. Mechanistically, Lp(a) may promote plaque instability through pro-inflammatory and pro-atherogenic effects. However, the relationship between Lp(a) levels, directly observed plaque vulnerability, and actual CCs release assessed by NOGA remains unclear.

Purpose

This study aimed to evaluate the association between Lp(a), aortic plaque vulnerability assessed by NOGA, and the detection of CCs in blood samples collected adjacent to plaques.

Methods

From September 2021 to December 2024, 144 patients with coronary artery disease who underwent NOGA were prospectively enrolled. A total of 350 plaque lesions in the infrarenal abdominal aorta were analyzed. For each lesion, blood samples (10 mL) were aspirated through a catheter above each plaque lesion. The presence of CCs was assessed using polarized light microscopy.

Patients were stratified according to lipid profiles and plaque characteristics: LDL-C ≥70 mg/dL; LDL-C ≥70 mg/dL with Lp(a) ≥50 mg/dL; and these conditions combined with the presence of RPs. Odds ratios (ORs) for CC detection were calculated using multivariable logistic regression models adjusted for clinical covariates.

Results

The mean age was 68 ± 10 years, and 84% were male. Median LDL-C was 65.0 [52.0–84.3] mg/dL, and median Lp(a) was 18.0 [10.5–49.5] mg/dL. RPs were identified in 77.8% of lesions. The likelihood of CC detection increased stepwise across risk categories. The OR was 1.70 for LDL-C ≥70 mg/dL, 2.13 for LDL-C ≥70 mg/dL with elevated Lp(a), and 3.29 when these lipid abnormalities coexisted with RPs. The highest odds were observed when all three conditions were present simultaneously.

Conclusions

Elevated Lp(a) and local plaque vulnerability assessed by NOGA were independently associated with increased CCs release beyond LDL-C levels. These findings provide mechanistic insight into residual lipid risk and suggest a potential pathway linking elevated Lp(a) to systemic embolic complications and distal organ injury.Cholesterol crystal detectionFor image description, please refer to the figure legend and surrounding text.Stepwise Increase in CC DetectionFor image description, please refer to the figure legend and surrounding text.