Produção Nacional
Revisado por pares
Prognostic utility of triglyceride-rich lipoprotein-related markers in patients with coronary artery disease
2020; Elsevier BV; Volume: 61; Issue: 9 Linguagem: Inglês
10.1194/jlr.ra120000746
ISSN1539-7262
AutoresYe‐Xuan Cao, Huiwen Zhang, Jing‐Lu Jin, Huihui Liu, Yan Zhang, Rui‐Xia Xu, Ying Gao, Yuan‐Lin Guo, Cheng‐Gang Zhu, Qi Hua, Yanfang Li, Raúl D. Santos, Na‐Qiong Wu, Jian‐Jun Li,
Tópico(s)Lipid metabolism and disorders
ResumoTG-rich lipoprotein (TRL)-related biomarkers, including TRL-cholesterol (TRL-C), remnant-like lipoprotein particle-cholesterol (RLP-C), and apoC-III have been associated with atherosclerosis. However, their prognostic values have not been fully determined, especially in patients with previous CAD. This study aimed to examine the associations of TRL-C, RLP-C, and apoC-III with incident cardiovascular events (CVEs) in the setting of secondary prevention of CAD. Plasma TRL-C, RLP-C, and total apoC-III were directly measured. A total of 4,355 participants with angiographically confirmed CAD were followed up for the occurrence of CVEs. During a median follow-up period of 5.1 years (interquartile range: 3.9–6.4 years), 543 (12.5%) events occurred. Patients with incident CVEs had significantly higher levels of TRL-C, RLP-C, and apoC-III than those without events. Multivariable Cox analysis indicated that a log unit increase in TRL-C, RLP-C, and apoC-III increased the risk of CVEs by 49% (95% CI: 1.16–1.93), 21% (95% CI: 1.09–1.35), and 40% (95% CI: 1.11–1.77), respectively. High TRL-C, RLP-C, and apoC-III were also independent predictors of CVEs in individuals with LDL-C levels ≤1.8 mmol/l (n = 1,068). The addition of RLP-C level to a prediction model resulted in a significant increase in discrimination, and all three TRL biomarkers improved risk reclassification. Thus, TRL-C, RLP-C, and apoC-III levels were independently associated with incident CVEs in Chinese CAD patients undergoing statin therapy. TG-rich lipoprotein (TRL)-related biomarkers, including TRL-cholesterol (TRL-C), remnant-like lipoprotein particle-cholesterol (RLP-C), and apoC-III have been associated with atherosclerosis. However, their prognostic values have not been fully determined, especially in patients with previous CAD. This study aimed to examine the associations of TRL-C, RLP-C, and apoC-III with incident cardiovascular events (CVEs) in the setting of secondary prevention of CAD. Plasma TRL-C, RLP-C, and total apoC-III were directly measured. A total of 4,355 participants with angiographically confirmed CAD were followed up for the occurrence of CVEs. During a median follow-up period of 5.1 years (interquartile range: 3.9–6.4 years), 543 (12.5%) events occurred. Patients with incident CVEs had significantly higher levels of TRL-C, RLP-C, and apoC-III than those without events. Multivariable Cox analysis indicated that a log unit increase in TRL-C, RLP-C, and apoC-III increased the risk of CVEs by 49% (95% CI: 1.16–1.93), 21% (95% CI: 1.09–1.35), and 40% (95% CI: 1.11–1.77), respectively. High TRL-C, RLP-C, and apoC-III were also independent predictors of CVEs in individuals with LDL-C levels ≤1.8 mmol/l (n = 1,068). The addition of RLP-C level to a prediction model resulted in a significant increase in discrimination, and all three TRL biomarkers improved risk reclassification. Thus, TRL-C, RLP-C, and apoC-III levels were independently associated with incident CVEs in Chinese CAD patients undergoing statin therapy. CAD persists as a leading cause of death in Western societies and in China (1Benjamin E.J. Muntner P. Alonso A. Bittencourt M.S. Callaway C.W. Carson A.P. Chamberlain A.M. Chang A.R. Cheng S. Das S.R. et al.Heart disease and stroke statistics-2019 update: a report from the American Heart Association.Circulation. 2019; 139: e56-e528Crossref PubMed Scopus (4871) Google Scholar). Elevated LDL-C is a well-established causal risk factor for CAD (2Wilson P.W.F. Polonsky T.S. Miedema M.D. Khera A. Kosinski A.S. Kuvin J.T. Systematic review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/ NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.Circulation. 2019; 139: e1144-e1161Crossref PubMed Scopus (59) Google Scholar). However, there is still a considerable residual risk of atherosclerotic cardiovascular events (CVEs) even after LDL-C lowering to recommended goals (3Mora S. Wenger N.K. Demicco D.A. Breazna A. Boekholdt S.M. Arsenault B.J. Deedwania P. Kastelein J.J. Waters D.D. Determinants of residual risk in secondary prevention patients treated with high- versus low-dose statin therapy: the Treating to New Targets (TNT) study.Circulation. 2012; 125: 1979-1987Crossref PubMed Scopus (121) Google Scholar). A growing amount of evidence supports the concept that elevated plasma TG-rich lipoproteins (TRLs) contribute to this residual risk (4Chapman M.J. Ginsberg H.N. Amarenco P. Andreotti F. Boren J. Catapano A.L. Descamps O.S. Fisher E. Kovanen P.T. Kuivenhoven J.A. et al.Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management.Eur. Heart J. 2011; 32: 1345-1361Crossref PubMed Scopus (937) Google Scholar, 5Bittencourt M.S. Santos R.D. Staniak H. Sharovsky R. Kondapally R. Vallejo-Vaz A.J. Ray K.K. Bensenor I. Lotufo P. Relation of fasting triglyceride-rich lipoprotein cholesterol to coronary artery calcium score (from the ELSA-Brasil Study).Am. J. Cardiol. 2017; 119: 1352-1358Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar). The cholesterol content of partially lipolyzed TRLs, also called remnant cholesterol (RC), includes cholesterol from either CMs or VLDL remnants, as well as from IDLs. RC can be classified into TRL-cholesterol (TRL-C) or remnant-like lipoprotein particle-cholesterol (RLP-C) (6Varbo A. Nordestgaard B.G. Remnant lipoproteins.Curr. Opin. Lipidol. 2017; 28: 300-307Crossref PubMed Scopus (54) Google Scholar). In view of the fact that TRL can be catabolized by macrophages, there is evidence that it is RC that promotes formation and progression of atherosclerosis rather than their TG content per se (7Sandesara P.B. Virani S.S. Fazio S. Shapiro M.D. The forgotten lipids: triglycerides, remnant cholesterol, and atherosclerotic cardiovascular disease risk.Endocr. Rev. 2019; 40: 537-557Crossref PubMed Scopus (149) Google Scholar). Indeed, experimental studies have shown that remnant lipoproteins can enter the intima of the arterial wall and be taken up by macrophages to induce foam cell formation (8Varbo A. Benn M. Nordestgaard B.G. Remnant cholesterol as a cause of ischemic heart disease: evidence, definition, measurement, atherogenicity, high risk patients, and present and future treatment.Pharmacol. Ther. 2014; 141: 358-367Crossref PubMed Scopus (138) Google Scholar). Several observational clinical studies, including ours, associated high RC concentrations with increased risk for CAD (4Chapman M.J. Ginsberg H.N. Amarenco P. Andreotti F. Boren J. Catapano A.L. Descamps O.S. Fisher E. Kovanen P.T. Kuivenhoven J.A. et al.Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management.Eur. Heart J. 2011; 32: 1345-1361Crossref PubMed Scopus (937) Google Scholar, 9Hong L.F. Yan X.N. Lu Z.H. Fan Y. Ye F. Wu Q. Luo S.H. Yang B. Li J.J. Predictive value of non-fasting remnant cholesterol for short-term outcome of diabetics with new-onset stable coronary artery disease.Lipids Health Dis. 2017; 16: 7Crossref PubMed Scopus (16) Google Scholar). Furthermore, evidence from Mendelian randomization studies indicated a causal association of RC with CAD development in previously healthy individuals (10Varbo A. Benn M. Tybjaerg-Hansen A. Jorgensen A.B. Frikke-Schmidt R. Nordestgaard B.G. Remnant cholesterol as a causal risk factor for ischemic heart disease.J. Am. Coll. Cardiol. 2013; 61: 427-436Crossref PubMed Scopus (629) Google Scholar, 11Rosenson R.S. Davidson M.H. Hirsh B.J. Kathiresan S. Gaudet D. Genetics and causality of triglyceride-rich lipoproteins in atherosclerotic cardiovascular disease.J. Am. Coll. Cardiol. 2014; 64: 2525-2540Crossref PubMed Scopus (156) Google Scholar). However, the prognostic value of plasma RC levels in secondary prevention settings is still undefined because previous studies showed inconsistent and controversial results (10Varbo A. Benn M. Tybjaerg-Hansen A. Jorgensen A.B. Frikke-Schmidt R. Nordestgaard B.G. Remnant cholesterol as a causal risk factor for ischemic heart disease.J. Am. Coll. Cardiol. 2013; 61: 427-436Crossref PubMed Scopus (629) Google Scholar, 12Jepsen A.M. Langsted A. Varbo A. Bang L.E. Kamstrup P.R. Nordestgaard B.G. 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However, no prospective data from a large sample size study is currently available concerning the association between plasma apoC-III and CVEs in patients with preexisting CAD. Furthermore, there is no evidence on how TRL-related biomarkers could modify CVE risk stratification in clinical practice on top of classical risk markers. Therefore, the aim of this prospective multicenter investigation was to test the prognostic value of directly measured plasma TRL-C, RLP-C, and total apoC-III levels for incident CVEs in a real-world setting of statin-treated Chinese patients with previous manifestation of CAD. Considering the heterogeneous nature of RLP-C, we used a simple and reliable method for its measurement as previously described (12Jepsen A.M. Langsted A. Varbo A. Bang L.E. Kamstrup P.R. Nordestgaard B.G. Increased remnant cholesterol explains part of residual risk of all-cause mortality in 5414 patients with ischemic heart disease.Clin. Chem. 2016; 62: 593-604Crossref PubMed Scopus (87) Google Scholar, 23Imke C. Rodriguez B.L. Grove J.S. McNamara J.R. Waslien C. Katz A.R. Willcox B. Yano K. Curb J.D. Are remnant-like particles independent predictors of coronary heart disease incidence? The Honolulu Heart study.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 1718-1722Crossref PubMed Scopus (63) Google Scholar). A total of 5,028 patients were consecutively enrolled due to angina-like chest pain that was confirmed as CAD by coronary angiography from three centers in China from May 2011 to February 2017. Participants were excluded from the study if they were aged <18 years, had familial hypercholesterolemia, or had severe chronic heart failure, thyroid dysfunction, severe liver and/or renal insufficiency, or malignant diseases. Patients without complete clinical data and blood samples were also excluded. All patients received guideline recommended pharmacological therapy for stable CAD (2Wilson P.W.F. Polonsky T.S. Miedema M.D. Khera A. Kosinski A.S. Kuvin J.T. Systematic review for the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/ NLA/PCNA guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines.Circulation. 2019; 139: e1144-e1161Crossref PubMed Scopus (59) Google Scholar). The study protocol was performed according to the Declaration of Helsinki and approved by the FuWai Hospital and National Center for Cardiovascular Diseases, Beijing, China review board. All study participants signed an informed consent. Clinical data of each participant were obtained by experienced physicians and nurses when first enrolled. CAD was defined as the presence of coronary stenosis with luminal diameter narrowing of 50% or more in any major coronary vessels detected by coronary angiography and assessed by two experienced physicians. BMI was calculated by dividing weight in kilograms by height in square meters. A diagnosis of hypertension was made when systolic and diastolic blood pressure were respectively greater than 140/90 mmHg or if subjects were taking antihypertensive medications. Diabetes was self-reported or considered present if one of four criteria were met: fasting plasma glucose level ≥7.0 mmol/l, 2 h plasma glucose of the oral glucose tolerance test ≥11.1 mmol/l, hemoglobin A1c level ≥6.5%, or use of oral antidiabetic medications or insulin injections. Information on other diseases, family history of CAD, and current therapy was self-reported or collected from medical record review as described previously (24Jin J.L. Cao Y.X. Zhang H.W. Sun D. Hua Q. Li Y.F. Guo Y.L. Wu N.Q. Zhu C.G. Gao Y. et al.Lipoprotein(a) and cardiovascular outcomes in patients with coronary artery disease and prediabetes or diabetes.Diabetes Care. 2019; 42: 1312-1318Crossref PubMed Scopus (57) Google Scholar). Blood samples were obtained from each patient from the cubital vein in the early morning after at least 12 h overnight fasting and stored at −80°C until analysis. The concentrations of plasma TG, total cholesterol (TC), HDL-C, apoAI, and apoB were directly measured using an automatic biochemistry analyzer (Hitachi 7150, Japan). The LDL-C concentration was analyzed by selective solubilization assay (LDL-C test kit; Kyowa Medex, Tokyo), while lipoprotein (a) [Lp(a)] concentration was assayed by an immunoturbidimetry method (24Jin J.L. Cao Y.X. Zhang H.W. Sun D. Hua Q. Li Y.F. Guo Y.L. Wu N.Q. Zhu C.G. Gao Y. et al.Lipoprotein(a) and cardiovascular outcomes in patients with coronary artery disease and prediabetes or diabetes.Diabetes Care. 2019; 42: 1312-1318Crossref PubMed Scopus (57) Google Scholar). Non-HDL-C was calculated as TC minus HDL-C. The concentration of high-sensitivity C-reactive protein (hsCRP) was measured by immunoturbidimetry (Beckmann Assay360; Bera, CA). Direct measurement of TRL-C was performed with a two-step automated assay (Denka Seiken Co., Ltd., Tokyo, Japan), determining the cholesterol content in CMs, VLDL, and IDL specifically as previously described (12Jepsen A.M. Langsted A. Varbo A. Bang L.E. Kamstrup P.R. Nordestgaard B.G. Increased remnant cholesterol explains part of residual risk of all-cause mortality in 5414 patients with ischemic heart disease.Clin. Chem. 2016; 62: 593-604Crossref PubMed Scopus (87) Google Scholar). Cholesterol in other lipoproteins is first removed by enzymes and surfactants, and then the cholesterol in the remaining lipoprotein particles is determined. Plasma RLP-C levels were determined by a high-sensitivity two-step fully automated homogeneous method (Denka Seiken Co., Ltd.), which was different from TRL-C, as previously reported (23Imke C. Rodriguez B.L. Grove J.S. McNamara J.R. Waslien C. Katz A.R. Willcox B. Yano K. Curb J.D. Are remnant-like particles independent predictors of coronary heart disease incidence? The Honolulu Heart study.Arterioscler. Thromb. Vasc. Biol. 2005; 25: 1718-1722Crossref PubMed Scopus (63) Google Scholar). Plasma total apoC-III concentration was measured by an immunoturbidimetric assay (Denka Seiken Co., Ltd.) and analyzed on a Hitachi 7180 automatic analyzer. The intra- and inter-assay coefficients of variation for these assays were all <6%. At baseline, lipid profiles of each participant were measured in triplicate and the mean value was used in the final analysis. Patients were followed up semiannually by clinic visits or by telephone interviews conducted by trained nurses or doctors. The primary endpoint was a composite of incident MI, ischemic stroke, unstable angina pectoris (UAP) requiring hospitalization, coronary revascularization, and cardiovascular death. MI was defined according to medical records showing typical chest pain, typical changes on the electrocardiogram, and elevated cardiac necrosis biomarkers, such as creatine kinase-MB and troponin-I (25Thygesen K. Alpert J.S. Jaffe A.S. Simoons M.L. Chaitman B.R. White H.D. Thygesen K. Alpert J.S. White H.D. Jaffe A.S. et al.Third universal definition of myocardial infarction.J. Am. Coll. Cardiol. 2012; 60: 1581-1598Crossref PubMed Scopus (2281) Google Scholar). Ischemic stroke was defined as a new-onset stroke diagnosed by computed tomography or magnetic resonance imaging during the follow-up period. A diagnosis of UAP was made by angina at rest or new-onset severe angina pectoris, presenting or not presenting changes on the electrocardiogram, without troponin elevation but requiring hospitalization. Revascularization was defined as percutaneous coronary intervention or coronary artery bypass grafting when myocardial ischemia was confirmed beyond 90 days after discharge. Diagnosis of cardiovascular death was confirmed by hospital records, death certificates, and information provided by family members. All events were counted as separate and unique. Thirty-eight patients (0.76%) were lost to follow-up, and therefore a total of 4,355 patients were included in the present study (supplemental Fig. S1). Continuous variables were expressed as mean ± SD or median with (interquartile range) when appropriate. Categorical variables were presented as number (percentage). Differences were assessed by Student's t-test and the Mann-Whitney U test, ANOVA, χ2 analysis, and Fisher's test as appropriate. The correlation between lipids, TRL-related biomarkers, and other biomarkers was evaluated by Pearson's correlation coefficients. Kaplan-Meier survival curves with log-rank test were applied. The association of TRL-related biomarkers with study endpoints was tested in univariate and multivariate Cox proportional hazard models with hazard ratios (HRs) and 95% CIs: model 1 was adjusted for age and sex; model 2 was additionally adjusted for traditional risk factors (BMI, current smoking, diabetes, baseline statin use, and family history of CAD, TC, LDL-C, HDL-C, TG, and hsCRP). Restricted cubic splines were calculated to assess the potential linearity relationship between TRL-related biomarkers and events. Subgroup analyses were performed to test the robustness of our findings. The incremental discrimination value of the addition of TRL-C, RLP-C, and apoC-III levels to classical risk biomarkers in risk prediction models were assessed by Harrell's C-statistic. Risk reclassification was tested by continuous net reclassification improvement (NRI) and integrated discrimination improvement (IDI) for survival data (26Leening M.J. Steyerberg E.W. Van Calster B. D'Agostino Sr., R.B. Pencina M.J. Net reclassification improvement and integrated discrimination improvement require calibrated models: relevance from a marker and model perspective.Stat. Med. 2014; 33: 3415-3418Crossref PubMed Scopus (39) Google Scholar). All statistical analyses were performed with SPSS version 24.0 software (SPSS Inc., Chicago, IL) and R version 3.5.2 (R Foundation for Statistical Computing, Vienna, Austria). Statistical significance was set as P < 0.05. The baseline clinical characteristics of the studied population are shown in Table 1. The mean age of participants was 58.21 ± 9.72 years, in which 71.1% (n = 3,096) were male. Compared with event-free patients, those with incident events were more likely to be older (59.57 ± 10.14 years vs. 58.01 ± 9.64 years, P = 0.001) and had higher levels of TG, TRL-C, RLP-C, apoC-III, and hsCRP at baseline, but did not differ with respect to sex and the prevalence of smoking, diabetes, and baseline statin use. There was no statistically significant difference in TC or LDL-C between the two groups.TABLE 1.Baseline characteristics of study patients presenting or not presenting CVEs during follow-upVariablesOverall (n = 4,355)With Event (n = 543)Without Event (n = 3,812)PAge, years58.21 ± 9.7259.57 ± 10.1458.01 ± 9.640.001Male sex, n (%)3,096 (71.1)370 (68.1)2,726 (71.5)0.105BMI, kg/m225.85 ± 3.1025.85 ± 2.9825.85 ± 3.120.998Family history of CAD, n (%)612 (14.1)69 (12.7)543 (14.2)0.335Currently smoker, n (%)2,354 (54.1)283 (52.1)2,071 (54.3)0.334Alcohol consumption, n (%)1,438 (33.0)161 (29.7)1,277 (33.5)0.740Hypertension, n (%)2,834 (65.1)372 (68.5)2,462 (64.6)0.073Diabetes, n (%)2,392 (54.9)290 (53.4)2,102 (55.1)0.447TC, mmol/l4.08 ± 1.054.16 ± 1.004.07 ± 1.060.061HDL-C, mmol/l1.06 ± 0.291.05 ± 0.281.06 ± 0.290.301LDL-C, mmol/l2.44 ± 0.902.48 ± 0.862.44 ± 0.900.251Non-HDL-C, mmol/l3.02 ± 1.003.11 ± 0.953.01 ± 1.010.038TG, mmol/l1.46 (1.09–2.02)1.54 (1.09–2.20)1.45 (1.08–2.01)0.008TRL-C, mmol/l0.50 (0.36–0.69)0.53 (0.38–0.74)0.50 (0.35–0.69)0.002RLP-C, mmol/l0.28 (0.15–0.54)0.33 (0.17–0.62)0.28 (0.14–0.52)0.001Lp(a), mg/dl15.12 (6.74–36.12)15.37 (7.64–34.57)15.03 (6.62–36.30)0.394ApoAI, mg/dl132.58 ± 28.93134.76 ± 29.85132.42 ± 28.790.325ApoB, mg/dl90.84 ± 29.0192.64 ± 27.6290.58 ± 29.200.122ApoC-III, mg/dl8.82 (6.68–11.6)9.19 (6.95–12.29)8.76 (6.65–11.48)0.003hsCRP, mg/l1.36 (0.73–2.87)1.64 (0.81–3.22)1.33 (0.72–2.82)0.002Glucose, mmol/l6.16 ± 2.006.27 ± 2.086.15 ± 1.990.193Hemoglobin A1C, %6.64 ± 1.226.75 ± 1.366.63 ± 1.200.087Previous medical history Prior angina, n (%)3,310 (76.0)422 (77.7)2,888 (75.8)0.318 Prior MI, n (%)990 (22.7)140 (25.8)850 (22.3)0.072 Prior revascularization, n (%)586 (13.5)75 (13.8)511 (13.4)0.795Medication use, n (%) ACEI or ARB, n (%)1,088 (25.0)126 (23.2)962 (25.2)0.306 Beta-blockers, n (%)3,481 (79.9)419 (77.2)3,062 (80.3)0.085 Aspirin, n (%)4,272 (98.1)528 (97.4)3,744 (98.2)0.202 Statins at baseline, n (%)2,647 (60.8)310 (57.1)2,337 (61.3)0.600 High-intensity,aHigh-intensive statin refers to atorvastatin ≥40 mg or rosuvastatin ≥20 mg. n (%)568 (13.0)79 (14.5)489 (12.8)0.265 Statin at follow-up, n (%)4,216 (96.8)521 (95.2)3,695 (96.9)0.228Data are expressed as the mean value ± SD, median and range (25th and 75th percentiles), or number (percent) of patients.a High-intensive statin refers to atorvastatin ≥40 mg or rosuvastatin ≥20 mg. Open table in a new tab Data are expressed as the mean value ± SD, median and range (25th and 75th percentiles), or number (percent) of patients. Baseline clinical characteristics stratified by the quintiles of plasma TRL-C, RLP-C, and apoC-III concentrations are presented in supplemental Tables S1–S3. Patients in the upper quintiles were youngest in age, more likely to be female, and had higher levels of BMI. Prevalence of statin therapy at baseline was less frequent in patients with higher TRL-C and RLP-C concentrations, whereas there was no similar trend toward apoC-III levels. The highest baseline LDL-C levels were seen in those in the highest quintiles of plasma TRL-C, RLP-C, and apoC-III. Correlations between plasma lipids and lipoproteins are presented in Fig. 1. There were moderate positive inter-correlations among TRL-C, RLP-C, and apoC-III. These three parameters were weakly correlated with LDL-C and apoB levels, but inversely correlated with HDL-C. During a median follow-up period of 5.1 years (interquartile range: 3.9–6.4 years), a total of 543 (12.5%) CVEs were observed, representing 24.7 (95% CI: 16.2–35.7) events per 1,000 person-years. Among the 543 patients with events, 132 (3.0%) had UAP requiring hospitalization, 44 (1.0%) had MI, 109 (2.5%) developed stroke, 183 (4.2%) underwent post-discharge percutaneous coronary intervention or coronary artery bypass grafting and 75 (1.7%) died. As shown in Fig. 2, Kaplan-Meier analysis demonstrated that patients in the highest quintiles of TRL-C, RLP-C, and apoC-III had a higher probability of developing incident CVEs compared with those in the lowest quintiles (all log-rank P < 0.005). Supplemental Fig. S2 also shows that patients with the highest levels of TG and non-HDL-C had the lowest total event-free survival rates. Figure 3 and supplemental Table S4 display the adjusted HRs for CVEs. Comparing top versus bottom quintile, TRL-C concentrations were positively and significantly associated with CVEs in univariate Cox regression analysis (HR: 1.49; 95% CI: 1.14–1.96). When adjusted for age and sex, the HR for CVEs was 1.55 (95% CI: 1.18–2.04) in quintile 5 compared with quintile 1. After additional adjustment for potential confounders, TRL-C remained significantly associated with incident CVEs (HR:1.53; 95% CI:1.16–2.02). Similar results were observed for patients with elevated levels of RLP-C (HR: 1.49; 95% CI: 1.12–2.09) and apoC-III (HR: 1.50; 95% CI: 1.13–2.01) after adjustment for multiple established cardiovascular risk factors. When the three parameters were analyzed as continuous variables, log-transformed TRL-C, RLP-C, and apoC-III were associated with 39% (HR: 1.39; 95% CI: 1.15–1.67), 19% (HR: 1.19; 95% CI: 1.09–1.32), and 44% (HR: 1.44; 95% CI: 1.18–1.77) higher risk of CVEs in univariate Cox regression analysis. The increase in risk per log increment in TRL-C, RLP-C, and apoC-III concentration after multifactorial adjustment were 1.49 (95% CI: 1.16–1.93), 1.21 (95% CI: 1.09–1.35), and 1.40 (95% CI: 1.11–1.77), respectively. Age- and sex-adjusted restricted cubic splines showed a nonlinear relation between the three parameters on continuous scales and the risk of CVEs (Fig. 3). Subgroup analyses were then performed according to clinical and laboratory characteristics (supplemental Fig. S3). When stratified by baseline median levels of hsCRP, multivariate Cox analysis revealed that only RLP-C and apoC-III tended to be positively associated with the risk of events in both hsCRP strata, while all three TRL-related biomarkers were significantly associated with CVEs in patients with LDL-C lower than 2.6 mmol/l. To further explore whether these three parameters were potential residual risk markers in patients with LDL-C ≤1.8 mmol/l (27Mach F. Baigent C. Catapano A.L. Koskinas K.C. Casula M. Badimon L. Chapman M.J. De Backer G.G. Delgado V. Ference B.A. et al.2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.Eur. Heart J. 2020; 41: 111-188Crossref PubMed Scopus (3066) Google Scholar), we conducted multivariate Cox regression analyses in 1,068 CAD patients with 123 events (Table 2). All three parameters were significantly associated with a higher rate of events when tested either as categorical or continuous variables.TABLE 2Multivariate Cox hazard analyses models for incident CVEs in CAD patients with LDL-C ≤1.8 mmol/l (n = 1,068)VariablesHR (95% CI)PTRL-C Per Log unit increase1.95 (1.33–2.86)0.001 Tertile 3 versus tertile 11.89 (1.21–2.97)0.006RLP-C Per Log unit increase1.30 (1.07–1.59)0.010 Tertile 3 versus tertile 11.71 (1.10–2.66)0.017ApoC-III Per Log unit increase1.57 (1.05–2.37)0.030 Tertile 3 versus tertile 11.54 (1.01–2.35)0.042Data are adjusted for age, sex, BMI, current smoking, diabetes, baseline statin use, family history of CAD, TC, LDL-C, HDL-C, TG, and hsCRP. Open table in a new tab Data are adjusted for age, sex, BMI, current smoking,
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