When metabolic syndrome (MetS) is diagnosed (Grundy et al., 2005), patients need to be accurately evaluated because of the higher risk of developing atherosclerotic cardiovascular disease (ASCVD). Carotid intima-media thickness (C-IMT) and plaques are the surrogate marker of atherosclerosis and powerful predictor of vascular outcomes in MetS patients (Pollex et al., 2006; Rundek et al., 2007; Olmastroni et al., 2019). However, the accuracy in the stratification of the carotid atherosclerosis (CA) severity is not satisfactory using only traditional risk factors. Lipoprotein(a) [Lp(a)] is a lipoprotein consisting of a particle of apolipoprotein B linked to apolipoprotein(a) and can be considered an “emergent” risk factor for the development of ASCVD and CA (Tsimikas, 2017) due to its pro-thrombotic and pro-inflammatory effects (Orso and Schmitz, 2017), at least when markedly elevated (Emerging Risk Factors et al., 2009; Kamstrup et al., 2009). Nevertheless, Lp(a) is not routinely measured in a real-world setting, at least in part because of the lack of standardization of the dosage methods and the absence of commercially available Lp(a)-lowering therapies. Anyway, it has been postulated that Lp(a) could be a useful tool in clinical practice for identifying patients in which the atherosclerotic process is more advanced (Ezhov et al., 2014; Rigamonti et al., 2018). Furthermore, second-generation anti-sense oligonucleotides designed to target and bind to apo(a) messenger RNA (mRNA) in hepatocytes are increasingly approaching clinical practice (Katzmann et al., 2020;Lp(a)HORIZON, 2022). Characterizing the role of Lp(a) in different classes of patients at cardiovascular risk is becoming an urgent need. Here, we focused on MetS, an enhancer of CA development (Cuspidi et al., 2018). The aim of this study was the evaluation of the independent association between Lp(a) and the CA severity in a group of patients with an established diagnosis of MetS.

Demographic, clinical, and anthropometric data on sixty-five patients with evidence of asymptomatic CA are summarized in Table 1. All patients were Caucasian and without history of familial hypercholesterolemia, the median age was 58 years old, 61.5% of patients were male, and 29.2% were current smokers. As expected, BMI and waist circumference were high (median values were 29.4 kg/m² and 105 cm, respectively), reflecting the typical accumulation of visceral adipose tissue in these kind of patients. It is worth noting that despite MetS criteria being well represented in the cohort, the median 10-year ASCVD risk was 1.8, which was considered moderate. Accordingly, only one patient had a clinical history of ASCV disease. Lp(a) values range from 1 to 192 mg/dl (Supplementary Figure S1).

Among those different CV risk factors, Lp(a) emerged as the only variable differing across the study groups (moderate vs. severe CA), as reported in Table 2. Indeed, despite a prevalence of males (65% vs. 56%) and smokers (7% vs. 12%) and, generally, a worse metabolic profile, only the levels of Lp(a) were significantly different [6 (2 to 12)] mg/dl vs. 11.5 (6 to 29.5)] mg/dl; p = 0.018. We also observed no differences in the pharmacological history of patients. In this regard, no patient was in active treatment with nicotinic acid and/or PCSK9 inhibitors.

In line with those observations, logistic regression analysis confirmed serum levels of Lp(a) as the only variable independently associated with severity of CA (Figure 1 and Supplementary Table S1) The OR for Lp(a) was indeed 2.9 with a 95% CI of 1.1–7.8. When the ROC curve was performed, a cut-off of 10 mg/dl was the best Lp(a) value, identifying patients with more severe atherosclerosis with an AUC of 0.675 (95% CI 0.548–0.786), a sensitivity of 69.0%, and a specificity of 70.4% (Figure 2).

The major finding of the present study was the independent association between Lp(a) levels and the severity of asymptomatic CA in a selected group of patients with an established diagnosis of MetS. As widely known, MetS represents a cluster of metabolic disturbances mainly derived from the accumulation of visceral adipose tissue, and it is mild but with chronic inflammation (Gustafson et al., 2007). This condition is strictly related to the higher risk of atherosclerosis, and several studies have documented the higher prevalence of CA in MetS patients (Grundy et al., 2005; Pollex et al., 2006). Lp(a) is increasingly described as an emerging contributor to the development of atherosclerotic plaque. Several pieces of experimental evidence have indeed demonstrated the pathogenetic role of Lp(a) in atherosclerosis due to its prothrombotic/anti-fibrinolytic effect and/or its ability to cross the endothelial barrier and accumulate in the arterial wall (Gustafson et al., 2007). Therefore, it seems that the longer the lifetime exposure to high Lp(a) plasma concentrations, the higher is the risk of ASCVD (Clarke et al., 2009; Kamstrup et al., 2009). Our results are somehow confirmative of this hypothesis even though the overall values are lower than values elsewhere reported.

In the present study, Lp(a) was shown to be the only independent variable discriminating two subgroups of patients categorized according to the severity of atherosclerotic lesions. Moreover, we were able to identify a relatively low cut-off value (10 mg/d), which could help at identifying subjects with higher C-IMTs or atherosclerotic plaques. We may also speculate about a future role of Lp(a)—even at low circulating levels—as a useful biomarker for implementing CV risk stratification. This could be applied in both primary and secondary CV prevention, combined with other recognized risk factors (as occurring in MetS).

We should acknowledge that the present study has many limitations. First, the small sample size does not allow in drawing any conclusion about clinical relevance of Lp(a) in CV risk stratification and the proportion of outlier. However, the cut-off point identified meets which were observed in the previous larger studies (Emerging Risk Factors et al., 2009; Rigamonti et al., 2018), and this may be considered a major strength of the present study.

Second, the use of nephelometric assay for the dosage of Lp(a) did not allow in evaluating the different apoprotein(a) [apo(a)] isoforms. It is indeed well-established that the lower the molecular weight of apo(a), the higher is the Lp(a) concentration and the risk of atherosclerotic disease (Kraft et al., 1996). Conversely, there is a lack of clinical evidence on how aggressive lipoprotein(a) lowering reduction improves the following ASCVD risk reduction. Attention should be then maintained on the other modifiable CV risk factors (Ruscica et al., 2021; Melita et al., 2022). Furthermore, we should acknowledge a considerable amount of outlier—especially toward higher values—that should affect statistical analysis. We then have to reaffirm that the findings have to be considered preliminary.

In conclusions, this study reported that even relatively low circulating Lp(a) may be useful in discriminating patients with more severe CA. Many ongoing clinical trials are called to confirm our preliminary observation, and they eventually identify whether Lp(a) might have a clinical use in CV risk stratification (NCT03887520, NCT04023552, and NCT04310917). They are also expected to identify Lp(a) as a potential biomarker useful to address therapeutic strategies toward a more aggressive approach.