This study aimed to investigate the impact of high-sensitivity C-reactive protein (hsCRP) on Lipoprotein(a) [Lp(a)] associated cardiovascular risk in patients with ST-segment elevation myocardial infarction (STEMI) underwent percutaneous coronary intervention (PCI). A total of 2318 STEMI-PCI patients were retrospectively recruited, and further stratified based on postprocedural hsCRP levels (≥ 2 vs < 2 mg/L). Major adverse cardiac events (MACE) were defined as all-cause death, myocardial infarction and stroke. During a mean follow-up of 2.5 years, MACE occurred in 159 (6.9%) patients. In the setting of hsCRP ≥ 2mg/L, per unit increase of Lp(a) was associated with a 28% increase of MACE risk (HR: 1.28, 95% CI: 1.09 to 1.49, p = 0.002; p = 0.031 for interaction); increasing tertiles of Lp(a) were significantly related to greater rates of MACE (p = 0.011 for interaction; p = 0.005 for trend across tertiles). Patients with upper tertile of Lp(a) had a significant lower event-free survival (p = 0.034) when hsCRP ≥ 2mg/L. No similar association between Lp(a) and MACE was noted when hsCRP < 2mg/L. In conclusion, high Lp(a) levels were associated with poor prognosis when hsCRP ≥ 2mg/L, implying systemic inflammation can modulate Lp(a)-associated MACE risk in STEMI-PCI patients. Measurement of Lp(a) in patients with high inflammation risk may identify individuals at high cardiovascular risk.
Lipoprotein(a) [Lp(a)] has been proved to a causal role in atherosclerosis, , and a major contributor to residual risk in optimally lipid-lowering treated patients. , Therefore, Lp(a) as an appropriate therapeutic target has attracted attentions in recent years. Lp(a)-lowering therapy, such as antisense oligonucleotides and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, has been confirmed to be effective in reducing the Lp(a) levels and cardiovascular risk. Systemic inflammatory activity, detected by the level of high-sensitivity C-reactive protein (hsCRP), was also a significant marker for adverse outcome among patients treated by PCI. , Synergism between Lp(a) and systemic inflammation for cardiovascular risk has been demonstrated in patients with high-risk vascular disease. However, it remains unclear whether hsCRP can modulate Lp(a)-associated cardiovascular risk in Chinese patients with ST-segment elevation myocardial infarction (STEMI) underwent Percutaneous Coronary Intervention (PCI). We sought to investigate the impact of hsCRP on Lp(a)-associated cardiovascular risk in Chinese STEMI-PCI patients.
Methods
A total of 3177 STEMI patients, from January 2012 to December 2017, undergoing emergent coronary angiography and PCI in Fuwai Hospital in Beijing, China, were consecutively included in the original cohort. We defined STEMI as continuous chest pain lasting > 30 min, ST-segment elevation of > 0.1 mV in at least 2 contiguous leads, or new left bundle-branch block on the 18-lead electrocardiogram and elevated troponin I level. Among these patients, 494 were lost to follow-up, 320 had missing hsCRP and Lp(a) test results, while another 45 were complicated with acute infection or inflammatory disorders. Finally, a total of 2318 STEMI patients treated by PCI were included into the current analysis, and furthermore stratified based on hsCRP levels (≥ 2 vs < 2 mg/L) according to prior study. This study complied with the Declaration of Helsinki and was approved by the hospital’s ethical review board (FuWai Hospital, Beijing, China). All subjects provided written informed consent during hospitalization about the use of clinical data for the purpose of scientific research.
Baseline information including demographics, medical history, physical examination, blood test results, echocardiography data, PCI-related factors and discharge medication use were reviewed. Hypertension was defined as repeated blood pressure measurements ≥ 140/90 mmHg for at least 3 times in different occasions or current use of anti-hypertensive medications. Diabetes mellitus (DM) was defined as glycated hemoglobin > 6.5%, a fasting serum glucose level ≥7.0 mmol/L, random glucose ≥ 11.1 mmol/L and/or use of hypoglycemic therapy. Dyslipidemia was defined by any of the following parameters: the total cholesterol (TC) ≥ 5.0 mmol/L, low-density lipoprotein cholesterol (LDL-C) ≥ 3.0 mmol/L or triglycerides (TG) ≥ 1.7 mmol/L (levels either pre-treatment or highest on treatment).
Blood samples for Lp(a) and hsCRP test were routinely collected via cubital vein after the PCI procedure (the next morning after patients were admitted into the coronary care unit) and after fasting for at least 12 hours. Blood testing was performed at the clinical laboratory in Fuwai Hospital. The level of hsCRP was measured using immunoturbidimetry (Beckmann Assay, Bera, California). Lp(a) was measured by an immunoturbidimetry method (LASAY lipoprotein(a) auto; SHIMA Laboratories Co., Ltd, Tokyo, Japan).
The endpoint was major adverse cardiac events (MACE), including all-cause death, recurrence of myocardial infarction and stroke. Outcome data was collected by outpatient visits or telephone interviews when Patients were routinely followed up at 1, 6, and 12 months after the discharge. For those who survived more than a year, the subsequent follow-up would be made annually.
Continuous variables are reported as mean ± standard deviation (SD) or median with interquartile range (IQR) and categorical variables were presented as number (percentage). Comparisons between continuous variables were performed by independent sample Student’s t test or Mann-Whitney U test and the chi-square test for categorical variables. Survival curves were constructed by the Kaplan–Meier method, and compared by the log-rank test. Univariate and multivariable Cox proportional hazards regression modeling was used to assess the relationship between MACE and Lp(a), including interactions, while adjusting for following covariates in an all-enter way: age, sex, hypertension, diabetes mellitus, total cholesterol, triglyceride, low-density-lipoprotein cholesterol and high-density lipoprotein-cholesterol. Hazard ratios and 95% CIs were reported. Tests of trend were performed across the Lp(a) tertiles. Analyses were conducted using IBM SPSS Statistics version 23.0 (IBM SPSS Statistics, IBM Corporation, Armonk, New York) and R ( http://www.r-project.org/ ) statistical packages. A p value < 0.05 was considered statistically significant.
Results
The baseline clinical characteristics were summarized in Table 1 . Among the 2318 STEMI-PCI patients, the mean age was 58.8 ± 11.9 years old, and 1850 (79.8%) patients were male. When stratified according to hsCRP levels, 1913 (82.5%) with hsCRP levels ≥ 2 mg/L and 405 (17.5%) had hsCRP levels < 2mg/L. Patients with higher hsCRP levels tended to be older, female and presented a higher BMI and more frequent of hypertension, thrombus aspiration and worse cardiac or renal function. Moreover, patients with hsCRP levels ≥ 2 mg/L vs < 2 mg/L were also more likely to present as dyslipidemia, with higher TC, TG, LDL-C and Lp (a) but lower HDL-C.
hsCRP (mg/L) | ||||
---|---|---|---|---|
Variable | Overall (n = 2318) | < 2 (n = 405) | ≥ 2 (n = 1913) | p value |
Age (years) | 58.8 ± 11.9 | 57.3 ± 11.2 | 59.1 ± 12.0 | 0.006 |
Men | 1850 (79.8%) | 345 (85.2%) | 1505 (78.7%) | 0.004 |
BMI (Kg/m 2 ) | 25.7 (23.6 -28.0) | 25.4 (23.2 – 27.7) | 25.8 (23.7 – 28.1) | 0.042 |
Hypertension | 1364 (58.8%) | 217 (53.6%) | 1147 (60.0%) | 0.021 |
Diabetes mellitus | 760 (32.8%) | 116 (28.6%) | 644 (33.7%) | 0.058 |
Dyslipidemia | 2001 (86.3%) | 334 (82.5%) | 1667 (87.1%) | 0.016 |
Current smoker | 1239 (66.7%) | 209 (70.4%) | 1030 (66.0%) | 0.165 |
Previous CABG | 21 (0.9%) | 5 (1.2%) | 16 (0.8%) | 0.631 |
Previous PCI | 317 (13.7%) | 58 (14.3%) | 259 (13.5%) | 0.736 |
Anterior wall MI | 939 (43.8%) | 173 (46.5%) | 766 (43.3%) | 0.279 |
Killip classes II-IV | 61 (2.8%) | 4 (1.1%) | 57 (3.2%) | 0.037 |
LVEF at admission (%) | 55.0 (50.0 – 59.0) | 57.5 (53.0 – 60.0) | 55.0 (50.0 – 59.0) | <0.001 |
Creatinine (umol/L) | 77.2 (67.4 – 89.1) | 73.6 (64.4 – 84.6) | 78.0 (68.2 – 90.5) | <0.001 |
TC (mmol/L) / (mg/dL) | 4.5 ± 1.1 | 4.3 ± 1.0 | 4.6 ± 1.1 | <0.001 |
174.7 ± 41.4 | 166.0 ± 39.6 | 176.5 ± 41.5 | ||
TG (mmol/L) / (mg/dL) | 1.4 (1.0 – 2.0) | 1.2 (0.7 – 1.7) | 1.5 (1.1 – 2.0) | <0.001 |
125.7 (89.4 – 175.3) | 105.4 (65.5 – 152.3) | 130.2 (93.9 – 180.6) | ||
LDL-C (mmol/L) / (mg/dL) | 2.8 ± 0.9 | 2.7 ± 0.9 | 2.8 ± 1.0 | 0.004 |
108.7 ± 36.5 | 104.1 ± 34.3 | 109.7 ± 36.9 | ||
HDL-C (mmol/L) / (mg/dL) | 1.1 (1.0 – 1.5) | 1.2 (1.0 – 1.6) | 1.1 (0.9 – 1.5) | 0.02 |
42.9 (35.6 – 59.1) | 45.2 (37.1 – 61.1) | 42.5 (35.2 – 58.4) | ||
Lp (a) (mg/dL) | 18.4 (8.8 – 36.4) | 14.1 (6.7 – 31.7) | 19.2 (9.4 – 37.4) | <0.001 |
hsCRP (mg/L) | 6.7 (2.7 – 11.8) | 1.3 (0.9 – 1.6) | 9.1 (4.2 – 12.2) | <0.001 |
No. of coronary arteries narrowed | 0.681 | |||
1 | 1230 (53.7%) | 213 (53.2%) | 1017 (53.8%) | |
2 | 447 (19.5%) | 84 (21.0%) | 363 (19.2%) | |
3 | 614 (26.8%) | 103 (25.8%) | 511 (27.0%) | |
Culprit coronary artery | 0.015 | |||
LM | 16 (0.7%) | 2 (0.5%) | 14 (0.7%) | |
LAD | 1078 (47.4%) | 199 (50.1%) | 879 (46.9%) | |
LCX | 303 (13.3%) | 47 (11.8%) | 256 (13.6%) | |
Right | 870 (38.3%) | 145 (36.5%) | 725 (38.6%) | |
Bypass graft | 6 (0.3%) | 4 (1.0%) | 2 (0.1%) | |
Thrombus aspiration | 1166 (53.9%) | 186 (48.8%) | 980 (55.0%) | 0.032 |
Pre-PCI TIMI 0 flow | 1505 (66.4%) | 235 (59.2%) | 1270 (67.9%) | 0.001 |
Post-PCI TIMI 3 flow | 2220 (98.0%) | 394 (99.2%) | 1826 (97.7%) | 0.074 |
Discharge medication | ||||
Aspirin | 1939 (90.5%) | 348 (93.5%) | 1591 (89.9%) | 0.036 |
P2Y12 inhibitors | 2115 (91.2%) | 372 (91.9%) | 1743 (91.1%) | 0.151 |
Statin | 2162 (93.3%) | 377 (93.1%) | 1785 (93.3%) | 0.871 |
Dosage of statin | 0.286 | |||
Double-dose | 952(41.1%) | 178(44.0%) | 774(40.5%) | |
Standard-dose | 1107(47.8%) | 177(43.7%) | 930(48.6%) | |
Half-dose | 103(4.4%) | 22(5.4%) | 81(4.2%) |
Table 2 describes univariable and fully adjusted multivariable relationships between MACE stratified according to hsCRP and Lp(a) levels. In the overall population, both higher hsCRP levels (≥ 2 vs < 2 mg/L) and higher Lp(a) levels (≥ median vs < median) were not associated with the risk of MACE. However, when stratifying the overall population according to hsCRP levels, higher Lp(a) levels were significantly associated with the risk of MACE only when hsCRP levels were 2 mg/L or more, per SD increase in the level of Lp(a) was associated with a 28% increase risk of MACE (HR: 1.28,95% CI: 1.09 to 1.49, p = 0.002). There was a significant interaction for MACE between continuous Lp(a) and the hsCRP dichotomy (p = 0.031 for interaction).