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1 These authors contributed equally to this study.
Deshan Yuan
Footnotes
1 These authors contributed equally to this study.
Affiliations
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
1 These authors contributed equally to this study.
Peizhi Wang
Footnotes
1 These authors contributed equally to this study.
Affiliations
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
Corresponding author. Department of Cardiology, Fu Wai Hospital National Center for Cardiovascular Diseases Chinese Academy of Medical Sciences No 167, Beilishi Road, Xicheng District, Beijing, 100037, China.
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
Corresponding author. Department of Cardiology, Fu Wai Hospital National Center for Cardiovascular Diseases Chinese Academy of Medical Sciences No 167, Beilishi Road, Xicheng District, Beijing, 100037, China.
National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, PR China
Elevated Lp(a) and hsCRP were individually associated with increased cardiovascular events risk.
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Association between Lp(a) and cardiovascular risk might be stronger in patients with higher hsCRP concentrations.
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Evaluation of Lp(a) and hsCRP concurrently may help risk stratification.
Abstract
Background and aims
In patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI), the effects of high-sensitivity C-reactive protein (hsCRP) on Lipoprotein(a) (Lp(a))-associated cardiovascular risk remains unclear. This study aimed to investigate the independent and combined association of Lp(a) and hsCRP with cardiovascular events in this specific population.
Methods
A total of 10,424 patients with measurements of both Lp(a) and hsCRP were included in this prospective cohort study. Cox proportional hazards models and Kaplan-Meier analysis were performed to evaluate the relationship between Lp(a), hsCRP and adverse cardiac and cerebrovascular events (MACCE; all-cause death, myocardial infarction, ischemic stroke and revascularization).
Results
During 5 years of follow-up, 2140 (20.5%) MACCE occurred. Elevated Lp(a) and hsCRP levels were associated with increased risks of MACCE (p<0.05). Notably, there might be a significant interaction between Lp(a) and hsCRP (P for interaction = 0.019). In the setting of hsCRP≥2 mg/L, significant higher risk of MACCE was observed with Lp(a) 15–29.9 mg/dL (HR: 1.18; 95% CI 1.01–1.39) and Lp(a) ≥30 mg/dL (HR: 1.20; 95% CI 1.04–1.39), whereas such association was attenuated when hsCRP was <2 mg/L with Lp(a) 15–29.9 mg/dL (HR: 0.94; 95% CI 0.80–1.10) and Lp(a) ≥30 mg/dL (HR: 1.12; 95% CI 0.98–1.28). Moreover, when Lp(a) and hsCRP were combined for risk stratification, patients with dual elevation of these two biomarkers had a significant higher risk of MACCE compared with the reference group (Lp(a) < 15 mg/dL and hsCRp<2 mg/L) (p<0.05).
Conclusions
In patients with CAD undergoing PCI, high Lp(a) level was associated with worse outcomes, and this association might be stronger in those with elevated hsCRP concomitantly. Evaluation of Lp(a) and hsCRP together may help identify high-risk individuals for targeted intervention in clinical utility.
Despite revascularization and optimal secondary prevention strategies, patients with coronary artery disease (CAD) remain at high risk of recurrent adverse events [
]. Therefore, identification of residual cardiovascular risk to tailor personal treatment approaches is critical in clinical practice. Lipoprotein(a) [Lp(a)] is a lipoprotein particle similar in structure to low-density lipoprotein cholesterol (LDL-C) and contributes to atherosclerosis, thrombosis and inflammation [
Lipoprotein(a): a genetically determined, causal, and prevalent risk factor for atherosclerotic cardiovascular disease: a scientific statement from the American heart association.
Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials.
]. High-sensitivity C-reactive protein (hsCRP) is an effective biomarker to ascertain inflammation levels. Anti-inflammatory therapies have been demonstrated to improve prognosis of CAD patients with elevated hsCRP levels [
]. Recently, several studies reported the synergistic effect of hsCRP with Lp(a) on cardiovascular risk. In patient with vascular disease, a post-hoc analysis from the ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes) trial indicated that Lp(a)-mediated cardiovascular risk was modulated by hsCRP levels [
Effect of C-reactive protein on lipoprotein(a)-associated cardiovascular risk in optimally treated patients with high-risk vascular disease: a prespecified secondary analysis of the ACCELERATE trial.
]. Similarly, the MESA (Multi-Ethnic Study of Atherosclerosis) study based on a primary prevention cohort reported that Lp(a) increased cardiovascular risk only in individuals with concomitantly elevated hsCRP [
However, in CAD patients undergoing percutaneous coronary intervention (PCI), information is limited about the association of Lp(a) and hsCRP with adverse cardiovascular events. We hypothesize that individuals with dual elevation of Lp(a) and hsCRP levels may have worse clinical outcomes. This study thereby aimed to investigate the independent and joint association of Lp(a) and hsCRP with long-term outcomes in patients with CAD based on a large secondary prevention cohort.
2. Patients and methods
2.1 Study population
Data from a prospective, observational cohort of the national tertiary care institute (Fuwai Hospital, Beijing) were analyzed in this study. A total of 10,724 patients undergoing PCI were consecutively enrolled at our center from January 2013 to December 2013. 10,424 patients with measurements of both Lp(a) and hsCRP were included in this analysis. Regular follow-up was achieved through outpatient visits, telephone interview and medical records at five time points (1-month, 6-month, 12-month, 2-year and 5-year after discharge). The primary endpoint was major adverse cardiac and cerebrovascular events (MACCE), a composite of all-cause death, myocardial infarction (MI), unplanned revascularization and ischemic stroke. All events were adjudicated centrally by 2 independent cardiologists, and disagreement was resolved by consensus. The Institutional Review Board approved the study protocol, which also complied with the Declaration of Helsinki, and the patients provided written informed consent before the intervention.
Overnight fasting blood samples were collected via cubital vein after admission within 24 h. For patients receiving emergency PCI, an additional blood sampling was performed at admission. Diabetes was diagnosed by fasting blood glucose (FBG) ≥7.0 mmol/L, or hemoglobin A1c levels≥6.5%, or 2-h blood glucose of oral glucose tolerance test ≥11.1 mmol/L [
]. Hypertension was diagnosed by systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg. Left main (LM) disease was defined as stenosis ≥50% in the left main coronary artery confirmed by coronary angiography. Likewise, three-vessel disease was diagnosed by stenosis ≥50% in all three main coronary arteries (left anterior coronary artery, left circumflex artery and right coronary artery). Details on the Lp(a) assay are provided in Supplemental methods. Briefly, Lp(a) was measured using the immunoturbidimetry method [LASAY Lipoprotein(a) auto; SHIMA laboratories Co., Ltd] with a normal value < 30 mg/dL. The latex beads were coated with polyclonal anti-human Lp(a) antibodies (goat) to react with Lp(a). The assay was calibrated by Lp(a) protein-validated lyophilized methods with a 5-point calibrator. The coefficient of variation value of intra- and inter-assay was 1.8% and 2.5%, respectively. The fresh sample was single measured on o clinical laboratory routine basis. hsCRP was measured using immunoturbidimetry (Beckmann Assay, Bera, California).
2.2 Statistical analysis
Continuous variables with normally or skewed distributions were summarized as mean ± SD and median (interquartile range), respectively. Categorical variables were presented as frequency and percentage. Differences of continuous and categorical variables in baseline characteristics were compared by unpaired Student's t-test or Mann-Whitney U test and chi-square test, as appropriate. Lp(a) and hsCRP were normalized by log transformation when analyzed as continuous variables. According to the guidelines, hsCRP levels exceeding 2 mg/L are defined as elevated [
ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American heart association task force on clinical practice guidelines.
]. The association between Lp(a) and the primary outcome was initially examined using restricted cubic splines with 3 knots at 10th, 50th and 90th centiles based on the Akaike information criterion, and the reference was the median value of Lp(a) (18.5 mg/dL). For categorical analysis, patients were divided into 2 groups according to the threshold of 30 mg/dL. Further, they were stratified into 3 groups (Lp(a) level＜15, 15–29.9, and ≥30 mg/dL) to evaluate the gradual relationship between Lp(a) and adverse events. The joint effects of Lp(a) and hsCRP on the primary outcome was subsequently analyzed by stratifying patients into 6 groups according to different Lp(a) and hsCRP levels. Kaplan-Meier curves were depicted to illustrate survival distributions and log-rank test was performed to compare difference among groups. Cox regression analyses were performed to estimate hazard ratios (HRs) and 95% confidence interval (CI). Interactions between Lp(a) and hsCRP were tested in the categories by adding Lp(a)*hsCRP to the Cox model. Proportional hazards assumption was verified by Schoenfeld residuals. The models including variables were as follows: age and sex (Model 1); Model 1 plus diabetes mellitus, hypertension, current/former smoker (Model 2); Model 2 plus LDL-C and eGFR (Model 3). Statistical analyses were conducted with SPSS version 25.0 (IBM Corp., Armonk, N.Y., USA). Figures were created using R version 4.0.0 (R Foundation for Statistical Computing, Vienna, Austria) and GraphPad Prism version 7.0.0 for Windows (GraphPad Software, San Diego, California USA). A two-tailored p value < 0.05 was considered statistically significant.
3. Results
3.1 Baseline characteristics and Lp(a) distribution of study population
Patients with elevated hsCRP were older, more likely female and had overall higher prevalence of cardiometabolic risk factors (e.g., diabetes mellitus, hypertension, smoking, higher levels of Lp(a), triglycerides, total cholesterol and LDL-C), more severe coronary artery disease (defined by SYNTAX score, left main and/or three vessels involved) and lower LVEF (Table 1). Moreover, patients with Lp(a) and hsCRP data available shared similar baseline characteristics with patients who did not (Supplemental Table 1). The distribution of Lp(a) was right-skewed with a median level of 18.5 mg/dL (interquartile range: 7.9 and 41.2 mg/dL). Moreover, 3632 (34.8%) patients and 6792 (65.2%) patients were at high (≥30 mg/dL) and low (30 mg/dL) Lp(a) levels, respectively (Fig. 1).
Table 1Baseline characteristics for patients classified by hsCRP.
3.2 Association of Lp(a) and hsCRP levels with MACCE
At 5-year follow-up, 2140 (20.5%) MACCE were observed among participants. Restricted cubic splines showed a monotonic increase in HRs for MACCE with higher Lp(a) levels (p for non-linearity>0.05) (Supplemental Fig. 1). Kaplan-Meier analysis demonstrated that patients with higher Lp(a) or hsCRP levels had a significantly increased risk of MACCE compared with those with lower ones (p<0.001) (Fig. 2A and B). Multivariable analyses were conducted to determine the association of Lp(a) and hsCRP with MACCE in three prespecified models. As showed in Table 2, elevated Lp(a) levels were significantly associated with higher risk of MACCE in the fully adjusted model when assessed by the threshold of 30 mg/dL (adjusted HR: 1.14; 95% CI 1.05–1.25; p<0.05). Similarly, a significant association was observed between MACCE and hsCRP when assessed by categorical threshold of 2 mg/L (adjusted HR: 1.10; 95% CI 1.01–1.20; p<0.05).
Fig. 2Kaplan-Meier analysis for major adverse cardiac and cerebrovascular events according to (A) Lp(a) (<30 or ≥30 mg/dL), (B) hsCRP (<2 or ≥2 mg/L).
3.3 Interrelationship between Lp(a) and hsCRP with MACCE
The gradual relationship between different Lp(a) levels and MACCE was further evaluated after patients were stratified into 3 groups (Lp(a) level <15, 15–29.9, and ≥30 mg/dL). Kaplan-Meier analysis showed that patients with Lp(a) ≥30 mg/dL had higher cumulative incidence of adverse events (p < 0.001, Fig. 3). Compared with the lowest Lp(a) category, multivariable analyses showed that Lp(a)≥30 mg/dL was associated with increasing MACCE risk (adjusted HR: 1.16; 95% CI 1.06–1.28; p < 0.05) in the model fully adjusted for age, sex and other ASCVD risk factors (Table 3). Notably, there might be a significant interaction for MACCE between Lp(a) and hsCRP (p for interaction = 0.019). In the setting of hsCRP ≥2 mg/L, significant risks of MACCE were observed with Lp(a) levels of 15–30 mg/dL (adjusted HR: 1.18; 95% CI 1.01–1.39; p < 0.05) and Lp(a) levels ≥30 mg/dL (adjusted HR: 1.20; 95% CI 1.04–1.39; p < 0.05), whereas such association among Lp(a) groups was attenuated for hsCRp <2 mg/dL (Fig. 4).
Fig. 3Kaplan-Meier analysis for major adverse cardiac and cerebrovascular events according to different Lp(a) levels (<15, 15–29.9, and ≥30 mg/dL).
Cox proportional hazards model was adjusted for age, sex, diabetes mellitus, hypertension, current/former smoker, LDL-C and eGFR. Point estimates of HRs and 95% CI are represented by the blue dots with horizontal lines. p value for interaction between Lp(a) and hsCRP = 0.019. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)
3.4 Joint associations of Lp(a) and hsCRP with MACCE
When patients were evaluated according to both Lp(a) (<15, 15–29.9, and ≥30 mg/dL) and hsCRP levels (<2 mg/L and ≥2 mg/L), Kaplan-Meier analyses showed that those with both high levels of Lp(a) and hsCRP had the lowest event-free survival rate among all the groups (p < 0.001, Fig. 5). Moreover, compared with the reference group (Lp(a) < 15 mg/dL and hsCRp <2 mg/L), multivariable analysis indicated that patients with Lp(a) levels 15–29.9 mg/dL and hsCRP≥2 mg/L (adjusted HR: 1.20; 95% CI 1.03–1.40; p<0.05), and patients with Lp(a)≥30 mg/dL and hsCRP≥2 mg/L (adjusted HR: 1.22; 95% CI 1.07–1.39; p<0.05) had a significant higher MACCE risk in the fully adjusted models (Table 4).
Fig. 5Kaplan-Meier analysis for major adverse cardiac and cerebrovascular events according to combined groups stratified by Lp(a) and hsCRP.
Based on a large secondary prevention cohort of patients with CAD undergoing PCI, the present study investigated the association of Lp(a) and hsCRP with adverse cardiovascular events during 5 years of follow-up. We found that Lp(a) and hsCRP levels were associated with higher risk of MACCE in the entire cohort population. Notably, there might be a significant interaction between Lp(a) and hsCRP. In the setting of hsCRP ≥2 mg/L, significantly higher risk of MACCE was observed in patients with elevated Lp(a) levels, whereas such association was attenuated among groups when hsCRp <2 mg/L. Moreover, compared with the reference group with low Lp(a) and hsCRP levels, individuals with dual elevation of Lp(a) and hsCRP levels suffered the highest residual risk, and thus, in theory, may benefit from further treatments than targeting Lp(a) and inflammation.
Over the past decades, advancement in the identification of modifiable risk factors has remarkedly improved clinical outcomes in the context of CAD. However, with aggressive contemporary secondary prevention managements, CAD patients still suffer from high incidence of future adverse events, suggesting that potential residual cardiovascular risks remain to be addressed [
Lipoprotein(a): a genetically determined, causal, and prevalent risk factor for atherosclerotic cardiovascular disease: a scientific statement from the American heart association.
]. In the setting of a secondary prevention population, higher baseline and on-statin Lp(a) levels were reported to be associated with increased risk of adverse events [
Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials.
]. In line with previous studies, the present study showed that elevated Lp(a) increased long-term risk of MACCE in CAD patients undergoing PCI. Data from the ODYSSEY and FOURIER trials demonstrated that exertion of inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) could further decrease adverse cardiovascular events by reducing Lp(a) levels even in those who achieved recommended LDL-C targets [
]. These findings support the hypothesis that targeting Lp(a) might bring incremental benefit in secondary prevention populations. However, it remains unclear whether Lp(a)-associated cardiovascular risk could be modified by other high-risk states. Identification of potential regulators of Lp(a)-associated risk might help optimize personalized therapeutic regimen.
Inflammation has also been recognized as an important contributor of residual cardiovascular risk [
]. The inspiring results of recent clinical trials on anti-inflammatory therapies constitute a powerful impetus to the discussion about residual inflammatory risk in CAD patients [
]. The CANTOS study demonstrated that anti-inflammatory therapies with canakinumab could significantly reduce hsCRP levels and adverse cardiovascular events in patients with a history of myocardial infarction (MI) and residual inflammation risk [
]. Similarly, the COLCOT study revealed that in individuals with recent MI, anti-inflammatory treatment with colchicine improved clinical outcomes in the presence of residual inflammation risk [
]. Subsequently, the favorable benefit from anti-inflammatory effects of colchicine was validated in patients with chronic coronary disease in the LoDoCo2 study [
]. Although the pathogenic role of residual inflammation in CAD is widely investigated, mainstream clinical treatment remains challenging given the scarcity, high cost and safety concerns of available anti-inflammatory agents.
Currently, evidence on the relationship between Lp(a) together with hsCRP and cardiovascular risk is limited. In primary prevention settings, Anne et al. found that the ability of elevated Lp(a) to predict ischemic heart disease and myocardial infarction in the general population was not affected by CRP levels [
]. The Bruneck Study based on a small general community sample suggested that elevated Lp(a) could predict long-term cardiovascular risk at different hsCRP levels [
]. Based on an observational cohort, the MESA study indicated that Lp(a)-associated cardiovascular risk in primary prevention population was modified by plasma hsCRP levels [
]. In secondary settings, it has been reported that joint assessment of residual cardiovascular risk including Lp(a) and hsCRP improved risk stratification in patients with chronic coronary syndrome [
Synergistic effect of the commonest residual risk factors, remnant cholesterol, lipoprotein(a), and inflammation, on prognosis of statin-treated patients with chronic coronary syndrome.
]. In addition, a prespecified post hoc secondary analysis of the ACCELERATE trial in patients with vascular disease suggested that Lp(a)-associated risk of adverse events was observed only in those with hsCRP levels 2 mg/L or higher [
Effect of C-reactive protein on lipoprotein(a)-associated cardiovascular risk in optimally treated patients with high-risk vascular disease: a prespecified secondary analysis of the ACCELERATE trial.
]. Similarly, a recent prospective cohort study found that Lp(a)-associated stroke recurrence risk was attenuated at low inflammation levels in patients with ischemic stroke or transient ischemic attack [
]. However, the predictive value of Lp(a) combined with hsCRP remains to be determined in patients with established CAD undergoing PCI. Our study found that the risk of cardiovascular events was significantly higher with elevated Lp(a), and this association might be stronger in the case of higher hsCRP concentrations. The categories of Lp(a) in this study were chosen with reference to previous studies [
Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials.
Predicting cardiovascular outcomes by baseline lipoprotein(a) concentrations: a large cohort and long-term follow-up study on real-world patients receiving percutaneous coronary intervention.
]. Previous studies reported that moderated elevation of Lp(a) in high-risk individuals, even if less than 30 mg/dL, had already conferred significant high ASCVD risk [
]. Therefore, we categorized patients into different groups with the cutoff of 15 and 30 mg/dL to provide more valuable information.
In the setting of primary prevention, hsCRP and Lp(a) have been recommended as biomarkers to refine risk stratification of CAD in the general population according to the American College of Cardiology (ACC)/American Heart Association (AHA) guidelines [
ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American heart association task force on clinical practice guidelines.
Guideline on the management of blood cholesterol: a report of the American College of Cardiology/American heart association task force on clinical practice guidelines.
]. In secondary prevention, recent evidence has suggested contemporary therapies might be inadequate to address residual cardiovascular risk driven by Lp(a), inflammation and other risk profiles [
Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials.
]. Therefore, it is imperative to identify potential individuals with residual risk who may benefit the most from further therapeutic interventions. The present study, along with prior studies [
Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials.
Effect of C-reactive protein on lipoprotein(a)-associated cardiovascular risk in optimally treated patients with high-risk vascular disease: a prespecified secondary analysis of the ACCELERATE trial.
], supports evaluation of Lp(a) and hsCRP levels in secondary prevention populations to guide decisions on the optimal use of medical treatments. Future studies are warranted to investigate whether therapies targeting Lp(a) and inflammation might be of incremental value beyond traditional treatments for prognostic improvement in high-risk individuals. Pelacarsen is an emerging agent that reduces Lp(a) levels remarkedly by targeting the LPA gene [
]. The ongoing Lp(a) HORIZON trial will answer whether pelacarsen therapy could bring favorable benefit in patients with cardiovascular disease (NCT04023552). In addition, the LPA gene has a known IL-6 response element, and IL-6 may play an important role in both elevation of Lp(a) and hsCRP levels through inflammatory pathways. The phase II RESCUE trial observed that inhibition of IL-6 reduced hsCRP as well Lp(a) in patients with residual inflammatory risk and chronic kidney disease [
]. Similarly, our findings may facilitate further explorations of whether CAD patients with high levels of hsCRP and Lp(a) would benefit the most from inhibition of IL-6.
Lp(a) is an LDL-like lipoprotein particle with apolipoprotein B covalently attached by apo(a) through a single disulfide bond. The pathogenic effect of Lp(a) on cardiovascular disease is believed to be pleiotropic [
]. Lp(a) may contribute to the development of atherosclerosis via its LDL-like moiety. The plasminogen-like apo(a) component, ranging dramatically in size due to LPA gene variation, has potentially prothrombotic effects. In addition to atherogenic effects, the oxidized phospholipid carried by Lp(a) could trigger the inflammatory response via interaction with pattern recognition receptors on immune cells [
]. The proinflammatory IL-1(+) genotypes have been previously reported to modulate Lp(a)-associated cardiovascular risk by upregulating inflammatory pathways [
].Therefore, in individuals with high levels of hsCRP and Lp(a), the comprehensive effects mediated by Lp(a) might be enhanced via systemic inflammation, hence resulting in increased risks of adverse events.
Prior studies conducted in Chinese patients only focused on the independent association of Lp(a) with cardiovascular risk, especially in some specific populations such as those with diabetes, chronic kidney disease and familial hypercholesterolemia [
]. However, the relationship between Lp(a), together with inflammation, and ASCVD risk in Chinese adults has not been investigated. This study appears to be the first to evaluate the separate and joint association of Lp(a) and hsCRP with cardiovascular risk in Chinese patients undergoing PCI. The novelty of our findings is that the association between Lp(a) and MACCE seems slightly stronger in patients with higher hsCRP concentrations than in those with lower ones and concomitant elevation of these biomarkers indicates worse clinical outcomes. From the perspective of clinical implications, assessing hsCRP in patients with elevated Lp(a) levels may help identify high-risk individuals most likely to benefit from comprehensive strategies such as aggressive lipid management and anti-inflammatory therapy, as novel Lp(a)-lowering agents have not yet been approved for clinical practice. It is worth mentioning that the East Asians tend to have lower Lp(a) levels in the stable populations globally [
Acute and long-term effect of percutaneous coronary intervention on serially-measured oxidative, inflammatory, and coagulation biomarkers in patients with stable angina.
], and this might partly explain the high prevalence of elevated Lp(a) observed in our study. Another issue to be discussed is the clinical impact of inflammation on Lp(a) concentrations. The Copenhagen General Population Study found that Lp(a) levels were significantly higher with elevated hsCRP although the increase was relatively small [
Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER trial (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin).
Strengths of our study include the prospective study design and large sample size, and long-term follow-up period. However, this study still has several limitations. First, Lp(a) and hsCRP levels were only evaluated at baseline and a relatively high prevalence of elevated Lp(a) was observed in our study. Given these biomarkers may be positive acute -phase reactants after ACS, serial dynamic measurements would enable more accurate risk prediction. Second, due to the observational design, potential confounders could not be adequately adjusted. Third, this study was conducted in Chinese patients undergoing PCI, and whether the findings could be extended to other demographic groups remains unknown. Fourth, the Lp(a) assay was calibrated with an Lp(a) protein-validated standard, traceable to the World Health Organization/International Federation of Clinical Chemistry and Laboratory Medicine International reference material. However, we did not investigate and cannot excluded that the assay measures apo(a) isoform-insensitive. Fifth, information on the intensity of statin and LDL-C level achieved during follow-up is not available. Sixth, the interaction analysis should be considered exploratory given the statistical power might not be sufficient. Future studies with larger sample size are necessary to verify our findings.
4.1 Conclusions
In conclusion, this study suggested that the association between Lp(a) and risk for cardiovascular events might be slightly stronger in case of higher hsCRP levels. Evaluation of Lp(a) and hsCRP concurrently may help identify high-risk individuals who would benefit the most from further therapeutic interventions.
Financial support
This work was supported by the National Natural Science Foundation of China (Grant number 81770365), the National Natural Science Foundation of China (Grant number 81900323), the National Clinical Research Center for Cardiovascular Diseases, Fuwai Hospital, Chinese Academy of Medical Sciences (Grant number NCRC 2020013); the CAMS Innovation Fund for Medical Sciences (grant number 2020-I2M-C&T-B-049).
CRediT authorship contribution statement
Deshan Yuan: Conception, Design, Writing – original draft. Peizhi Wang: Writing – original draft. Sida Jia: Data collection and analysis, Data curation, Formal analysis. Ce Zhang: Data collection and analysis, Data curation, Formal analysis. Pei Zhu: Data collection and analysis, Data curation, Formal analysis. Lin Jiang: Data collection and analysis, Data curation, Formal analysis. Ru Liu: Data collection and analysis, Data curation, Formal analysis. Jingjing Xu: Data collection and analysis, Data curation, Formal analysis. Xiaofang Tang: Data collection and analysis, Data curation, Formal analysis. Ying Song: Data collection and analysis, Data curation, Formal analysis. Yi Yao: Data collection and analysis, Data curation, Formal analysis. Na Xu: Data collection and analysis, Data curation, Formal analysis. Yin Zhang: Conception, Design. Xueyan Zhao: Conception, Design. Yuejin Yang: Conception, Design. Bo Xu: Conception, Design. Lijian Gao: Conception, Design. Zhan Gao: Conception, Design. Runlin Gao: Conception, Design. Jinqing Yuan: Conception, Design, Reviewing and editing, Writing – review & editing.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
We thank all staff members for data collection, data analysis, and the efforts to cooperate with each other to finish the study.
Appendix A. Supplementary data
The following is the Supplementary data to this article:
Lipoprotein(a): a genetically determined, causal, and prevalent risk factor for atherosclerotic cardiovascular disease: a scientific statement from the American heart association.
Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials.
Effect of C-reactive protein on lipoprotein(a)-associated cardiovascular risk in optimally treated patients with high-risk vascular disease: a prespecified secondary analysis of the ACCELERATE trial.
ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American heart association task force on clinical practice guidelines.
Synergistic effect of the commonest residual risk factors, remnant cholesterol, lipoprotein(a), and inflammation, on prognosis of statin-treated patients with chronic coronary syndrome.
Predicting cardiovascular outcomes by baseline lipoprotein(a) concentrations: a large cohort and long-term follow-up study on real-world patients receiving percutaneous coronary intervention.
Guideline on the management of blood cholesterol: a report of the American College of Cardiology/American heart association task force on clinical practice guidelines.
Acute and long-term effect of percutaneous coronary intervention on serially-measured oxidative, inflammatory, and coagulation biomarkers in patients with stable angina.
Lipoprotein(a) concentrations, rosuvastatin therapy, and residual vascular risk: an analysis from the JUPITER trial (justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin).
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