The major findings of the present study are as follows: (1) Lp(a) was a significant independent predictor associated with necrotic core progression during statin therapy; (2) patients with necrotic core progression had higher fibro-fatty plaque volume and less necrotic core and dense calcium plaque volumes at baseline than patients with regression; and (3) 62% of patients treated with statin showed necrotic core progression during an 8-month follow-up period.
Lp(a) is a recognized risk factor for cardiovascular disease [16, 17]. Mechanisms that account for the association of Lp(a) with cardiovascular disease have been considered to be its structural similarity to plasminogen which could cause competition with plasminogen activators ; intraluminal thrombus formation may also cause a proliferative response of the vascular wall. A recent report supports its role as a prothrombotic factor in that Lp(a) appears to be significantly associated with carotid artery occlusion but not plaque size . However, Helgadottir et al. reported a stronger association of Lp(a) with atherosclerosis than with thrombosis . Furthermore, Lp(a) is associated with plaque progression, as indirectly assessed based on lumen changes on angiography [21, 22]. Although there are few data directly demonstrating a relationship between serum Lp(a) and coronary atherosclerosis, serum Lp(a) is an independent predictor of plaque progression . A consensus paper issued Lp(a) as a causal risk factor for cardiovascular disease, and recommended screening for Lp(a) in patients judged to be at high risk for future cardiovascular disease . Indeed, Lp(a) is associated with future cardiovascular events  and an adverse prognosis . Our study, therefore, supports the likelihood that Lp(a) is a good predictor of future cardiovascular events, because serum Lp(a) is associated with necrotic core progression during statin therapy.
The underlying mechanisms by which Lp(a) contributes to the pathogenesis of atherosclerosis are not fully understood . The pathophysiologic role of Lp(a) in atherosclerotic disease progression is explained by the accumulation of Lp(a) in the vessel wall, and its ability to promote cholesterol accumulation in macrophages forming foam cells and subsequent fatty streaks [28, 29]. Kiechl et al. reported a strong correlation between circulating Lp(a) levels and oxidized phospholipid/apolipoprotein B complex which suggested that Lp(a) transported the proinflammatory burden of oxidized phospholipids . The atherogenicity of Lp(a) may be mediated in part by associated proinflammatory oxidized phospholipids, and is associated with angiographically documented coronary artery disease . A recent study has documented that Lp(a) and oxidized phospholipids mediated macrophage apoptosis . Since macrophage apoptosis is a key component of plaque vulnerability, these phenomena may lead to necrotic core progression as observed in this study. Thus, Lp(a) may mediate antifibrinolytic, proinflammatory, and proapoptotic effects, including those potentiated by its content of oxidized phospholipids .
There is no consensus regarding the effects of statins on the necrotic core component [7–10]. Thus, the accumulation of necrotic core could not be halted with statin therapy in all patients. These differences may have occurred because of lipophilic and hydrophilic statins because lipophilic pitavastatin promotes oxidant stress-induced apoptosis of vascular smooth muscle cells, whereas hydrophilic pravastatin does not [7, 33]. In addition, statin therapy could not halt the increase in plaque vulnerability in patients with unstable angina pectoris . The differences of types of statin and subject population could account for these discrepancies. Indeed, pitavastatin use and unstable angina pectoris was associated with necrotic core progression on univariate regression analyses.
Additional important results of the present study were that 62% of patients treated with statin had necrotic core progression during an 8-month follow-up period and this may associate with future cardiovascular events as previously reported . In addition, plaques with greater fibro-fatty and less necrotic core component were prone to necrotic core progression during statin therapy. These results are consistent with previous reports that the fibro-fatty component is a reversible step of atherosclerosis [7, 8, 36]. As observed in this study, Lp(a) concentration is not influenced by statin therapy . However, Lp(a) is also the dominant risk factor for the severity and progression of coronary artery disease in patients treated with statins , our results support these reports. Intensive lipid-lowering therapy with statins reduces the risk of coronary events ; however, there is a residual risk. This implies a role for Lp(a) in being one of the potential etiologies for the presence of residual cardiovascular risk, and increases the priority for investigation of Lp(a) as a potential therapeutic target. Niacin was able to reduce serum Lp(a) levels [39, 40], and niacin added to simvastatin decreased carotid intima-media thickness , whereas no incremental clinical benefit was observed from the addition of niacin to statin therapy . Further studies are necessary to investigate better therapeutic options in statin-treated patients with high Lp(a) levels.
This study has several limitations. First, it was a post-hoc subanalysis and the results of this study may be biased because all subjects were treated with statins. However, this study demonstrate that the residual risk of cardiovascular events during statin therapy can be explained in part by Lp(a). Second, although we excluded patients with angiographically apparent thrombi, an intramural thrombus might have influenced the study results. In addition, the IVUS examination was performed in only the non-culprit lesions in the culprit vessel. Mechanical interventions might have affected the atheroma measurement. Furthermore, although VH-IVUS is a promising new diagnostic tool for visual interpretation of plaque characterization, it is not a substitute for pathologic sampling. Nair et al. reported that dividing a plaque into 4 distinct tissue components was difficult because of the presence of amorphous overlapping zones . Third, although Lp(a) appears to act an acute-phase reactant under some situation [43, 44], we could not analyze the subjects with stable and unstable angina pectoris separately because of statistical power. Finally, this study is limited by the relatively small number of patients.