1 Introduction

Acute coronary syndromes (ACS) are a leading cause of morbidity and mortality worldwide, claiming for approximately 9 million deaths annually [1-3]. Interestingly, despite advances in therapeutic interventions and secondary prevention strategies, such as high-intensity statin therapy or anti-inflammatory drugs, patients with ACS continue to face a significant residual cardiovascular risk, leaving them vulnerable to future cardiovascular events [4, 5].

Extensive evidence has shown that the progression and destabilization of atherosclerotic plaques are complex pathological processes involving numerous factors beyond low-density lipoprotein cholesterol (LDL-C) [6, 7]. As a result, the identification of novel proatherogenic risk factors, beyond traditional ones, has been and currently is a key research focus.

Among inflammatory markers, lipoprotein(a) (Lp(a)) has emerged as an independent and causal risk factor for atherosclerotic cardiovascular disease [8]. Lp(a) is an apoB100-containing lipoprotein bound to apolipoprotein(a). Its levels are genetically determined, show slight variation across the lifespan, and are unaffected by lifestyle or other biomarkers [9, 10]. The hypothesis suggests that Lp(a) may contribute to atherosclerosis through its lipoprotein component and to thrombosis via the plasminogen-like apo(a) part. Additionally, it may play distinct proinflammatory effects due to the generation of oxidized phospholipids, which are key triggers for the activation of the NLRP3 inflammasome and subsequent cytokine cascade [11, 12]. For these reasons, it has been explored and is currently under investigation as a target for primary and secondary prevention, including emerging therapies such as PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors and antisense oligonucleotides directly targeting apolipoprotein(a) [13, 14]. Nevertheless, the association of Lp(a) with specific plaque characteristics at intravascular imaging, has not been fully understood. Therefore, we aimed to clarify the influence of Lp(a) levels on plaque morphology as assessed by OCT in the very high-risk subset of patients hospitalized for ACS.

2 Methods

2.2 OCT Analysis

Intravascular OCT imaging was performed before and after PCI using a frequency domain OCT system (ILUMIEN OPTIS, St. Jude Medical/Abbott, St. Paul, MN, USA) and a Dragonfly catheter (Lightlab Imaging Inc., Westford, MA, USA). All pullbacks were analyzed offline, accurately examining plaque characteristics in pre-PCI pullbacks and assessing stent deployment results after PCI. The standardized procedure was as follows: after placing the 6 or 7 Fr guiding catheter and wiring the culprit lesion, the OCT catheter was advanced distally to the target lesion. Once the lesion length and minimal lumen area (MLA) were identified, a qualitative assessment of the coronary lesion was performed at the MLA. The following measurements were recorded: mean lipid arc and lipid length, mean calcium arc and calcium length, presence of macrophages, cholesterol crystals, intimal vasculature, and thin-cap fibroatheroma (TCFA). Based on these measurements, coronary plaques were classified as lipid-rich, fibrous, or calcific. In cases with borderline characteristics, we defined the plaque according to the predominant pattern. TCFA was defined as a fibrous cap < 65 microns overlying a large lipid-rich necrotic core [17]. Examples of plaque characteristics observed during OCT evaluation are provided in Figure 1.

3 Results

3.1 Baseline Clinical and Procedural Characteristics

After considering the selection criteria, 202 of the 295 ACS patients who underwent OCT-guided PCI at our catheterization laboratory were included in the analysis (19.8% female, mean age 67.17 ± 11.27 years). Among these, 107 (52.9%) had low Lp(a) levels, while 95 (47.1%) exhibited elevated Lp(a) values. Baseline characteristics are fully displayed in Table 1. Patients with elevated Lp(a) were slightly younger, with a mean age of 65.55 ± 12.61 years and most commonly presented with NSTEMI or unstable angina. The prevalence of cardiovascular risk factors and comorbidities was similar between the two groups, with no relevant differences observed. However, at laboratory evaluation, patients with Lp(a) ≥ 300 mg/L demonstrated a more altered lipid profile, showing higher mean total cholesterol (163.19 ± 65.88 vs. 142.77 ± 37.69 mg/dL in the low Lp(a) group) and mean LDL-C levels (104.27 ± 62.65 vs. 82.62 ± 35.16 mg/dL in the low Lp(a) group).

Table 1. Baseline characteristics stratified according to Lp(a) levels. Values are mean (± standard deviation) or n (%).

	Lp(a) < 300 mg/L N = 107 (52.9%)	Lp(a) $\mathit{\ge }$ 300 mg/L N = 95 (47.1%)	p value
Patient demographics
Age, years	68.79 ± 9.94	65.55 ± 12.61	0.043
BMI, kg/m2	25.96 ± 4.79	25.51 ± 4.95	0.513
Female sex	18 (16.8%)	22 (23.16%)	0.342
Medical history
Current smoker	38 (35.5%)	28 (29.5%)	< 0.001
Former smoker	25 (23.4%)	23 (24.2%)	0.658
Family history of CAD	39 (36.4%)	36 (37.9%)	0.947
Diabetes mellitus	32 (29.9%)	28 (29.5%)	0.946
Hypertension	76 (71.0%)	69 (72.6%)	0.923
Hyperlipidemia	25 (23.4%)	23 (24.2%)	0.980
Peripheral artery disease	7 (6.5%)	3 (3.2%)	0.434
Cerebrovascular disease	2 (1.9%)	0 (0%)	0.086
COPD	7 (6.5%)	5 (5.3%)	0.932
Chronic kidney disease	4 (3.7%)	9 (9.5%)	0.136
Prior PCI	18 (16.8%)	15 (15.8%)	0.967
Prior MI	15 (14.0%)	19 (20.0%)	0.705
Prior CABG	2 (1.9%)	0 (0%)	0.530
Laboratory
Glucose mg/dL	104.01 ± 36.30	119.43 ± 70.82	0.050
HbA1c mmol/mol	42.65 ± 5.18	44.00 ± 10.22	0.229
Serum creatinine, mg/dL	0.9 ± 0.20	1.05 ± 0.7	0.069
Total cholesterol, mg/dL	142.77 ± 37.69	163.20 ± 65.88	0.007
Low-density lipoprotein, mg/dL	82.6 ± 35.2	104.3 ± 62.6	0.002
High-density lipoprotein, mg/dL	45.6 ± 14.2	47.02 ± 11.7	0.443
Triglycerides, mg/dL	108.5 ± 41.1	110.5 ± 49.1	0.747
Lp(a), mg/L	98.1 ± 8.9	424.6 ± 11.2	< 0.001
Clinical presentation			0.440
STEMI	20 (18.7%)	14 (14.7%)
NSTEMI	44 (41.1%)	40 (42.1%)
Unstable angina	43 (40.2%)	41 (43.2%)
Admission medication
Aspirin	66 (61.7%)	61 (64.2%)	0.708
DAPT	58 (54.1%)	52 (54.7%)	0.782
Statins	73 (68.2%)	60 (63.2%)	0.646
Beta-blockers	66 (61.7%)	54 (56.8%)	0.578
Ace-inhibitors	45 (42.1%)	45 (47.4%)	0.538

• Abbreviations: BMI, body mass index; CABG, coronary artery bypass graft; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; DAPT, dual antiplatelet therapy; Lp(a), lipoprotein(a); MI, myocardial infarction; PCI, percutaneous coronary intervention.

As shown in Table 2, no significant differences in procedural characteristics were seen. Most of the procedures were performed via radial access (93.5% and 91.6%, in patients with low and elevated Lp(a) respectively); a large proportion of patients presented with single vessel disease, while around 30% exhibited two-vessel involvement; a consistent proportion of patients showed in-stent restenosis, bifurcation involvement, and moderate/severe calcification in both groups. No significant differences were detected in peri-procedural and in-hospital complications as displayed in Supporting Information S1: Table S1.

Table 2. Baseline procedural characteristics stratified according to Lp(a) levels. Values are mean (± standard deviation) or n (%).

	Lp(a) < 300 mg/L N = 107 (52.9%)	Lp(a) $\mathit{\ge }$ 300 mg/L N = 95 (47.1%)	p value
Procedural characteristics
Radial access	100 (93.5%)	85 (89.4%)	0.461
Femoral access	7 (6.5%)	10 (10.6%)	0.309
Lesions and PCI characteristics
Left main	16 (14.9%)	12 (12.6%)	0.785
CAD 1 vessel	53 (49.5%)	48 (50.5%)	0.077
CAD 2 vessels	31 (28.9%)	36 (37.9%)	0.077
CAD 3 vessels	18 (16.8%)	6 (6.3%)	0.077
Bifurcation	12 (11.2%)	10 (10.5%)	0.014
Chronic total occlusion	1 (0.9%)	0 (0%)	0.014
Moderate/severe calcification	18 (16.8%)	5 (5.3%)	0.014
Intrastent restenosis	11 (10.3%)	12 (12.6%)	0.600
Number OCT identified lesion
1	90 (84.1%)	73 (76.8%)	0.468
2	15 (14.0%)	18 (18.9%)	0.468
3	2 (1.9%)	3 (3.2%)	0.468
Treated with PCI	91 (85%)	78 (82.0%)	0.582
Predilatation	69 (64.5%)	63 (66.3%)	0.837
Single stent PCI	48 (44.9%)	38 (40.0%)	0.590
Multiple stent PCI	32 (29.9%)	26 (27.4%)	0.590
PCI with drug-eluting balloon	7 (6.5%)	11 (11.6%)	0.467
Fluoroscopy time (min)	20.4 ± 11.4	18.4 ± 10.7	0.209
Contrast (vol)	173.6 ± 60.4	168.0 ± 63.8	0.529
OCT assessment of the culprit lesion
Plaque rupture	26 (24.3%)	30 (31.6%)	0.474
Plaque erosion	14 (13.1%)	20 (21.0%)	0.277
Thrombus	4 (3.7%)	6 (6.3%)	0.757
Prevalent plaque type
Lipid plaque	31 (29.0%)	62 (65.3%)	0.002
Fibrous plaque	9 (8.4%)	5 (5.3%)	0.379
Calcific plaque	61 (57.0%)	17 (17.9%)	< 0.001
Minimum lumen area, mm2	2.8 ± 1.37	2.98 ± 1.90	0.507
Mean lipid arc (°)	88.45 ± 11.6	146.14 ± 12.42	< 0.001
Mean lipid length (mm)	6.21 ± 1.02	11.24 ± 1.16	< 0.001
Lipidic arc > 180°	19 (17.8%)	41 (43.2%)	0.001
TCFA	13 (12.2%)	22 (23.2%)	0.061
Presence of macrophage	33 (30.8%)	43 (45.3%)	0.049
Cholesterol crystals	47 (43.9%)	44 (46.3%)	0.842
Microvasculature	50 (46.7%)	31 (32.6%)	0.058
Mean calcium arc (°)	139.41 ± 12.39	68.82 ± 10.26	< 0.001
Calc length > 0.5 mm	27 (65.9%)	14 (34.1%)	< 0.001
Calc length > 1 mm	41 (68.3%)	19 (31.7%)	< 0.001
Fujino score
Fujino score 1	6 (5.6%)	3 (3.2%)	< 0.001
Fujino score 2	14 (13.1%)	3 (3.2%)	< 0.001
Fujino score 3	5 (4.7%)	2 (2.1%)	< 0.001
Fujino score 4	27 (25.2%)	11 (11.6%)	< 0.001

• Abbreviations: CAD, coronary artery disease; LM, left main; Lp(a), lipoprotein(a); OCT, optical coherence tomography; PCI, percutaneous coronary intervention.

4 Discussion

Several studies have demonstrated the association between elevated Lp(a) levels and the extent of coronary artery disease [18, 19]; however, limited evidence is available regarding the relationship between Lp(a) and atherosclerotic plaque phenotype detected at intravascular imaging. To the best of our knowledge, this is the largest study to offer a comprehensive OCT assessment of culprit plaque characteristics in a high-risk subset of patients, such as those undergoing PCI for ACS, stratified by Lp(a) levels. Our results align with previous literature based on different imaging techniques such as coronary computed tomography angiography or intravascular ultrasound which have suggested a role of Lp(a) in plaque progression and destabilization [20, 21]. Among these, Niccoli et al. showed a predominance of lipid-rich plaques in patients with high Lp(a) levels in a small cohort of 51 ACS patients undergoing OCT-guided coronary angiography [22]. Similarly, a post hoc analysis of 6 randomized trials identified Lp(a) as a reliable predictor of plaque atheroma volume detected with intravascular ultrasound, supporting its proatherogenic contribution to cardiovascular risk [23].

Interestingly, our analysis revealed a predominance of vulnerable plaque features, such as macrophage infiltration and TCFA, in subjects with Lp(a) levels ≥ 300 mg/L, further reinforcing the evidence of Lp(a)'s proinflammatory effects alongside its established proatherogenic role. This finding is consistent with a large translational study that demonstrated a strong association between elevated Lp(a) and increased arterial wall inflammation, as measured by multiple imaging modalities, including magnetic resonance, positron emission tomography/computed tomography, and single photon emission computed tomography/computed tomography, along with enhanced expression of proinflammatory genes in monocytes [24].

These combined proatherogenic and inflammatory effects, which contribute to both lipid-plaque enrichment and increased plaque vulnerability, might stem from the dual composition of Lp(a): a single molecule of apolipolipoprotein B-100 and the plasminogen-like apo(a) moiety [10]. Indeed, apo(B) may be the primary responsible for driving atherosclerosis progression due to its similarity to LDL [25]. On the other hand, oxidized phospholipids, present either in the lipid phase of Lp(a) or bound to apo(a), play a critical role in promoting monocyte trafficking by triggering cytokine production and facilitating monocyte entry into the vessel wall through monocyte chemoattractant protein-1, which is directly exposed to Lp(a)'s surface [26, 27].

Finally, we observed a negative association between older age and lipid-rich plaques, along with a higher prevalence of calcified plaques in patients with low Lp(a) levels. This contrasts with existing evidence suggesting a procalcific effect of Lp(a), revealing a potential inconsistency in our analysis that warrants further investigation in larger cohorts [28, 29]. A potential explanation for both these findings could be the slightly older age observed in patients with low Lp(a) levels along with the more frequent use of statin therapy in this cohort, both of which are well-known contributors to the calcification process [30, 31].

Overall our results have significant implications for improving diagnostic accuracy and guiding pharmacological treatment. Traditionally, Lp(a) has been regarded as a secondary target in patients experiencing cardiovascular events despite aggressive lipid-lowering therapies. However, beyond the well-established linear relationship between elevated Lp(a) and ASCVD risk, a high rate of risk reclassification has been shown in patients with very high Lp(a) levels, even in the absence of ASCVD identifying individuals who could benefit from early treatment [32]. Therefore, Lp(a) should be integrated into risk stratification and as a therapeutic target—not only at the time of PCI when patients are already at very high risk and exhibit more unstable plaques as in our analysis, but also during early screening to implement primary preventive measures. So far, studies showing potential benefits from Lp(a) apheresis have fueled ongoing research into specific Lp(a)-targeting interventions, such as antisense oligonucleotides, small interfering RNA-based therapies, and oral agents [14, 33, 34]. Further research is needed to clarify Lp(a)'s contribution to residual cardiovascular risk—both alone and in combination with other biomarkers—and to determine how best to incorporate it into widely used risk prediction and stratification tools. Additionally, future studies should refine the enrollment criteria to include not only high-risk patients but also those in earlier stages, and explore Lp(a) as a potential target for primary prevention.

5 Limitations

Our study has several limitations that should be considered for a correct interpretation of the results. First, its observational nature, combined with the relatively small sample size, data collection from a single PCI center and the absence of a standardized threshold for Lp(a) may limit the external validity of our findings. Second, despite being reviewed by two independent expert operators, the interpretation of OCT runs remains subjective, introducing potential bias. Third, the OCT analysis was confined to the culprit vessel, limiting the generalizability of our conclusions to other coronary vessels. Moreover, pre-PCI OCT was often performed after vessel recanalization with thrombectomy or thrombus aspiration and/or gentle balloon dilatation, which may have introduced bias in the accurate assessment of some culprit plaque features, including plaque rupture, plaque erosion, and thrombus. Finally, we did not collect detailed data on medications other than the use of statins, such as their dosage, duration, and type, which could have provided additional insights given their influence on plaque progression and calcification.

6 Conclusion

In this real-world cohort of ACS patients undergoing OCT-guided PCI, those with elevated Lp(a) levels (≥ 300 mg/L) exhibited a higher prevalence of lipid-rich plaques, increased macrophage infiltration, and thin-cap fibroatheroma, thereby indicating a more vulnerable plaque phenotype. Additionally, elevated Lp(a) levels and LDL-C levels ≥ 70 mg/dL were each independently associated with lipid-rich plaques. This underscores the significance of considering Lp(a) alongside LDL-C in improving risk stratification and guiding personalized treatment strategies to optimize outcomes in this high-risk patient population.

Conflicts of Interest

The authors declare no conflicts of interest.