The present study demonstrated a strong and independent relationship between fasting RLP-C levels and adverse prognosis in patients with NSTE-ACS treated with PCI. Further subgroup analyses elucidated that RLP-C showed a better predictive value in the diabetic population. However, RLP-C failed to be a significant determinant of adverse prognosis in the pre-diabetic and non-diabetic populations. The addition of the RLP-C level had a significant incremental effect on the predictive value for adverse events.
It has been widely demonstrated that LDL-C is one of the most significant risk indicators for ASCVD, and reduction of serum LDL-C levels with statins is a well-established therapy to reduce the ASCVD risk. However, many patients whose LDL-C levels are well controlled by statins continue to suffer recurrent cardiovascular events [3-7]. In recent years, factors related to obesity and metabolic syndrome, such as triglycerides rich lipoproteins (TRLs), have been considered as potential metabolism-related risk factors for cardiovascular diseases and a possible cause of residual risks other than LDL-C. As the cholesterol component of the subset of TRLs, RLP-C has been demonstrated to be a causal risk factor for ischemic heart disease (IHD) [23-25]. Clinical studies also revealed that higher RLP-C levels showed favorable predictive value for the risk of recurrent cardiovascular events in patients with either stable coronary artery disease (SCAD) or ACS, regardless of the baseline treatment of statins and level of LDL-C [12, 26-29]. The current analyses extend these findings to a cohort of patients with NSTE-ACS treated with PCI and indicate that elevated RLP-C is significantly associated with adverse prognosis.
Previous studies have also demonstrated the significant association of RLP-C with plaque characteristics of the coronary arteries, such as plaque burden, composition, and vulnerability. Lina et al. revealed that RLP-C levels were significantly related to coronary atherosclerotic burden evaluated by computed tomography coronary angiography (CTCA), even in patients with optimal LDL-C levels [30]. Puri et al. demonstrated that non-HDL-C levels were closely correlated with the progression and regression of atherosclerotic plaque burden assessed by intravascular ultrasound (IVUS), independent of LDL-C levels [31]. Matsuo et al. found that in statin-treated patients, RLP-C levels, as opposed to LDL-C levels, were strongly associated with the proportion of plaque necrosis (a marker of plaque vulnerability) evaluated by IVUS [32]. These findings provide important confirmation and interpretation of results from previous clinical studies, suggesting that a high RLP-C level is one of the risk factors for cardiovascular events. Additionally, this correlation between RLP-C and plaque characteristics was observed in the statin-treated and optimal LDL-C level group, indicating that high RLP-C levels may be a residual risk factor in the statin-treated population.
In this study, the LDL-C level did not show predictive value for poor prognosis, which was consistent with previous studies [5, 13, 29]. The underlying causes can be complex. Firstly, most participants that were enrolled in the present study underwent statin therapy, whose lipid-lowering effects in conjunction with other effects may have potential impacts on the association of LDL-C levels with adverse events. Moreover, patients with complex coronary lesions or clinical conditions may be inclined to receive more intensive lipid-lowering therapy. Such treatment selection bias or so-called “confounding by indication” may have a certain influence on the predictive ability of LDL-C. Additionally this may lead to a paradox phenomenon, such as the phenomenon that the use of angiotensin-converting enzyme inhibitors (ACEI) could predict adverse events, which was also present in our study. The present study revealed that RLP-C levels remained a predictor of adverse prognosis despite the probable influence of statin treatment on RLP-C levels, which indicated that RLP-C may have greater atherogenicity than other serum lipid parameters. TGs, TC, and HDL-C lost their predictability in the multivariate Cox proportional hazard analysis using covariates, including RLP-C, in the present study; which can partly be attributed to the strong correlation between them and RLP-C levels.
Results from previous studies have revealed that the impact of RLP-C seems to be more prominent in high-risk patients, such as those with metabolic syndromes or type 2 diabetes [12-16]. Our study also shows that RLP-C has predictive value for poor outcomes only in patients with diabetes, which indicates that there is significant interaction between glycometabolic status and RLP-C level on the risk of an adverse prognosis. Diabetic patients have more complex lipid metabolism disorders than non-diabetic patients characterized by increased TGs levels and decreased HDL-C levels [33]. Therefore, in addition to LDL-C, other lipid-metabolic indicators may also have a certain impact on the cardiovascular risk of diabetic patients. Previous studies have proven that hypertriglyceridemia and high TRLs play an important role in the development of coronary artery disease (CAD) [2, 4, 9]. TGs is predominantly carried by TRLs, which binds to arterial endothelium, where lipoprotein lipase initiates TGs hydrolysis, finally leading to the production of remnant lipoproteins. Thus, the concentrations of TGs are closely related to the cholesterol content of remnant lipoproteins, that is, RLP-C [34, 35]. The association of RLP-C with the TGs level was also verified in the present study. Studies have also shown that RLP-C levels increased in patients with diabetes compared with non-diabetic patients [12, 26, 35], which was consistent with our study. These phenomena may magnify the predictive value of RLP-C for adverse prognosis in patients with recognized diabetes.
Several pathophysiologic mechanisms may account for the association between high RLP-C levels and the increased prevalence of recurrent adverse events which was observed in the current study. These include: (1) RLP-C can upregulate the expression of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in endothelial cells, which further induces the migration of monocytes into the arterial wall [36]; (2) RLP-C increases the generation of tissue factors (TF), which is essential for the formation of thrombus in vessels [36]; (3) There is evidence that RLP-C can enhance the aggregation of platelets [37]; (4) RLP-C promotes the propagation of smooth muscle cells that is independent from the impact of oxidative stress [38]; (5) RLP-C is causally related to low-grade inflammation, with a nearly three-fold increase in CRP level for each 1 mmol/L increase in RLP-C [39]; (6) RLP-C was demonstrated to be a risk indicator for endothelial vasomotor dysfunction [16, 40]; and (7) High concentrations of RLP-C were proven to be correlated to inflammation in the arterial wall in cases of endothelial injury [41]. The pro-inflammatory and pro-atherothrombotic roles of RLP-C listed above may be the explanation for the relationship between high RLP-C levels and future adverse prognosis observed in the current study.
Studies have shown that less than a quarter of patients exhibited an LDL-C level below the guideline-recommended target, despite remaining on statin therapy during the secondary prevention period [28, 42]. This so-called “treatment gap” between the target value and clinical practice is common in the real world. In this context, while regarding LDL-C as the primary target, the exploration of residual risk factors can also provide complementary therapeutic strategies for reducing cardiovascular risk. The relationship between high RLP-C levels and increased incidence of recurrent adverse events in diabetic patients with NSTE-ACS treated with PCI demonstrated by the present study shows that RLP-C may be a complementary risk predictor and therapeutic target.
Previous reports showed that lipid-lowering agents, such as fibrates, ezetimibe, and statins, as well as diet adaptation, proper aerobic exercise, and obesity reduction, may effectively decrease RLP-C levels to varying degrees [26, 43, 44], thus enabling RLP-C as a therapeutic target. However, in addition to statin treatment for LDL-C, it is uncertain whether RLP-C should be a therapeutic target in recognized CAD patients. Clinical trials of non-statin, lipid-lowering treatments have shown significant benefit in reducing residual risk, but none have specifically targeted RLP-C. Newer agents, such as potent omega-3 fatty acid derivatives [45] or antisense oligonucleotide to apolipoprotein C-III [46], were proven to have the potential to reduce TRLs significantly and may provide useful tools for answering this question. In JELIS (Japan EPA Lipid Intervention Study), eicosapentaenoic acid (an omega-3 fatty acid derivative) combined with low-dose statins reduced triglycerides by about 5% and coronary events by 19% compared to low-dose statins alone [47]. Novel inhibitors of apolipoprotein C-III, a key regulator of remnant metabolism, have also shown promising results [48]. Furthermore, antibodies to PCSK9, although primarily intended to lower LDL-C concentrations, was also proven to reduce the cholesterol contained in TRLs to some extent [49].
Nowadays, the pattern of targeting LDL-C alone has changed, with recent guidelines highlighting the important role of non-high-density lipoprotein cholesterol (non-HDL-C), which includes RLP-C, on the pathogenesis of atherosclerosis and thus its availability as an additional therapeutic target [11]. Therefore, it is necessary to develop new therapies targeting RLP-C and conduct randomized trials evaluating whether lowering the RLP-C level can regulate plaque morphology and reduce the residual risk of substantial cardiovascular events.
The major strengths of present study were the long-term follow-up period and the large number of the enrolled subjects. This observational cohort study also expanded the relationship between RLP-C and poor outcomes to a specific cohort of patients with NSTE-ACS undergoing PCI. Additionally, the prognosis impact of RLP-C was evaluated in patients with differing glucose metabolic status. However, there are some limitations to our study: (1) Remnant lipoproteins mainly contain VLDL and chylomicron remnants. In the fasting state of the present study, VLDL remnants are the major constituent of circulating remnants, so that the contribution of chylomicron remnants to atherosclerosis and plaque burden may have been underestimated [50]. (2) Although potentially not as accurate as direct measurement, calculated remnant cholesterol as used in our study can be easily performed on a standard lipid profile without any additional cost. (3) Although evidence-based statin treatment was administrated, no specific statin agent or dose was specified. (4) Finally, although sequential surveillance may provide more information, only baseline lipid profiles before PCI were obtained in our study.