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Participant characteristics are summarized (Table 1). The mean age of the 2,031 participants was 60.4 years and 73.6% were male. Mean Lp-PLA2 levels were 168.5 ng/mL. Observed Lp-PLA2 level quartiles were: Quartile 1 (< 131.9 ng/mL), Quartile 2 (131.9–141.0 ng/mL), Quartile 3 (141.0–159.1 ng/mL), and Quartile 4 (≥ 159.1 ng/mL). We observed significant differences in age, income status, smoking status, drinking status, BMI, hs-CRP level, and history of hypertension between Lp-PLA2 quartiles. Lp-PLA2 levels showed an increased trend with age. Also, hs-CRP levels tended to be increased in the higher Lp-PLA2 quartile groups (Q4). In addition, we observed a tendency for more participants with hypertension in higher Lp-PLA2 quartile groups.
Characteristics Total Lp-PLA2 (ng/mL) P value Quartile 1
(< 131.9)Quartile 2
(131.9–141.0)Quartile 3
(141.0–159.1)Quartile 4
(≥ 159.1)n, % 2,031 509 (25.0) 507 (25.0) 508 (25.0) 507 (25.0) Age (years) 60.4 ± 11.7 55.7 ± 8.7 58.0 ± 10.2 61.7 ± 11.6 66.3 ± 13.1 < 0.001 Male (n, %) 1,495 (73.6) 384 (75.4) 379 (74.8) 363 (71.5) 369 (72.8) 0.460 Income, ¥/month (n, %) < 0.001 ≤ 3,000 1,697 (83.6) 459 (90.2) 428 (84.4) 420 (82.7) 390 (76.9) 3,001–5,000 252 (12.4) 44 (8.6) 65 (12.8) 66 (13.0) 77 (15.2) > 5,000 82 (4.0) 6 (1.2) 14 (2.8) 22 (4.3) 40 (7.9) Physical activity (n, %) 0.900 Inactive 749 (36.9) 192 (37.7) 185 (36.5) 181 (35.6) 191 (37.7) Moderately active 463 (22.8) 123 (24.2) 116 (22.9) 112 (22.1) 112 (22.1) Very active 819 (40.3) 194 (38.1) 206 (40.6) 215 (42.3) 204 (40.2) Smoking status (n, %) < 0.001 Never 1,099 (54.1) 246 (48.3) 260 (51.3) 303 (59.7) 290 (57.2) Ex-smoker 157 (7.7) 34 (6.7) 37 (7.3) 32 (6.3) 54 (10.7) Current smoker 775 (38.2) 229 (45.0) 210 (41.4) 173 (34.1) 163 (32.2) Drinker (n, %) 792 (39.0) 210 (41.3) 219 (43.2) 179 (35.2) 184 (36.3) 0.020 BMI (kg/m2) 0.020 < 24.0 796 (39.2) 179 (35.2) 183 (36.1) 206 (40.6) 228 (45.0) 24.0–27.9 923 (45.5) 244 (47.9) 235 (45.4) 230 (45.3) 214 (42.2) > 28.0 312 (15.4) 86 (16.9) 89 (17.6) 72 (14.2) 65 (12.8) Hypertension (n, %) 675 (33.2) 129 (25.3) 150 (29.6) 189 (37.2) 207 (40.8) < 0.001 Diabetes (n, %) 229 (11.3) 47 (9.2) 55 (10.9) 69 (13.6) 58 (11.4) 0.180 Hyperlipidemia (n, %) 245 (12.1) 62 (12.2) 68 (13.4) 63 (12.4) 52 (10.3) 0.480 hs-CRP (mg/dL) 2.5 ± 4.5 2.1 ± 3.3 2.3 ± 4.0 2.3 ± 4.0 3.1 ± 6.3 0.002 hs-CRP, mg/dL (n, %) 0.510 < 1.0 908 (44.7) 231 (45.4) 232 (45.8) 233 (45.9) 212 (41.8) ≥ 1.0 1,123 (55.3) 278 (54.6) 275 (54.2) 275 (54.2) 295 (58.2) Note. Values for categorical variables are represented as number (percentage); values for continuous variables are represented as the mean ± standard deviation. Lp-PLA2 = lipoprotein-associated phospholipase A2; BMI = body mass index; hs-CRP = high-sensitivity C-reactive protein. Table 1. Baseline characteristics of study participants according to serum Lp-PLA2 quartiles
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The median follow-up period was 9.1 years (IQR: 8.7–9.3 years). In total, 389 events were identified during the follow-up period, including 137 strokes (6.8%), 43 MIs (2.1%), and 244 all-cause deaths (11.9%). Strokes (137; 6.8%) included, 125 CIs (6.2%), 11 CHs (0.5%), and 3 SAHs (0.1%). With increasing Lp-PLA2 quartiles, the event rate of composite endpoints showed an upward trend. Q4 had the highest composited event rate (28.6%) when compared with Q1 (10.8%), Q2 (14.8%), and Q3 (22.4%). The accumulative incidence of predefined events during the follow-up period is shown (Figure 1).
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Kaplan-Meier cumulative risk curves for outcomes according to Lp-PLA2 quartiles are shown (Figure 2). Patients in higher Lp-PLA2 groups (Q4) had a significantly higher risk of all four outcome types (all Log-Rank P < 0.05). The HRs with 95% CIs for outcomes according to Lp-PLA2 level quartiles are shown (Table 2). When compared with the lowest Lp-PLA2 quartile, the HR with a 95% CI for developing composite endpoints was 1.77 (1.24–2.54) in the highest quartile. When compared with the lowest quartile, the HR with a 95% CI of the highest quartile (Q4) for developing incident stroke, MACE, and all-cause death was 1.92 (1.03–3.60), 1.69 (1.003–2.84), and 1.94 (1.18–3.18), respectively.
Figure 2. Cumulative risk of outcomes during a median follow-up of 9.1 years in the study population. Kaplan-Meier cumulative risk curves for composite endpoints (A), stroke (B), MACE (C), and all-cause death (D) in participants with different serum Lp-PLA2 levels. Lp-PLA2 Q1(-Q4) = lipoprotein-associated phospholipase A2 Quartile 1 (- Quartile 4); MACE = Major adverse cardiovascular events
Characteristics Events (n, %) Crude model
HR (95% CI)Model 1
HR (95% CI)Model 2
HR (95% CI)Composite endpoint Quartile 1 55 (10.8) Reference Reference Reference Quartile 2 75 (14.8) 1.19 (0.83−1.71) 1.22 (0.85−1.75) 1.20 (0.83−1.75) Quartile 3 114 (22.4) 1.36 (0.98−1.89) 1.42 (1.02−1.99) 1.37 (0.96−1.94) Quartile 4 145 (28.6) 1.60 (1.16−2.20) 1.74 (1.23−2.46) 1.77 (1.24−2.54) Stroke Quartile 1 22 (4.3) Reference Reference Reference Quartile 2 30 (5.9) 1.39 (0.77−2.53) 1.38 (0.76−2.52) 1.40 (0.74−2.63) Quartile 3 45 (8.9) 1.51 (0.87−2.64) 1.53 (0.88−2.69) 1.50 (0.82−2.76) Quartile 4 40 (7.9) 1.79 (1.002−3.19) 1.83 (1.01−3.33) 1.92 (1.03−3.60) MACE Quartile 1 31 (6.1) Reference Reference Reference Quartile 2 43 (8.5) 1.16 (0.71−1.91) 1.19 (0.72−1.95) 1.18 (0.71−1.97) Quartile 3 54 (10.6) 1.36 (0.85−2.17) 1.41 (0.88−2.26) 1.36 (0.82−2.26) Quartile 4 52 (10.3) 1.62 (1.004−2.61) 1.73 (1.04−2.87) 1.69 (1.003−2.84) All-cause death Quartile 1 28 (5.5) Reference Reference Reference Quartile 2 37 (7.2) 1.24 (0.75−2.06) 1.32 (0.79−2.20) 1.42 (0.82−2.44) Quartile 3 68 (13.4) 1.30 (0.83−2.04) 1.42 (0.90−2.26) 1.47 (0.89−2.42) Quartile 4 111 (21.8) 1.54 (1.01−2.36) 1.78 (1.13−2.82) 1.94 (1.18−3.18) Note. Model 1: Adjustments made for age and gender. Model 2: Adjustments made for age, gender, body mass index (BMI), drinker status, smoking status, history of hypertension, hyperlipidemia, diabetes, and hs-CRP. Bold HR (95% CI) indicates statistical significance. Lp-PLA2 = lipoprotein-associated phospholipase A2; MACE = Major adverse cardiovascular events; HR = hazard ratio; CI = confidence interval; hs-CRP = high-sensitivity C-reactive protein. Table 2. Association of serum Lp-PLA2 levels with outcomes in participants
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In subgroup analyses (Table 3), when compared with participants in the lowest Lp-PLA2 quartile, an increased risk of composite outcome in the highest quartile was statistically significant in males [Q4 vs. Q1: HR 1.91 (1.27–2.88)] but not significant in females (Pinteraction = 0.01). In addition, a significant association was also observed in participants aged > 65 years [Q2 vs. Q1: HR 2.05 (1.01–4.13); Q3 vs. Q1: HR 2.68 (1.37–5.22); and Q4 vs. Q1: HR 2.78 (1.43–5.40)], but not significant in participants aged < 65 years (Pinteraction = 0.04). In subgroup analyses based on hs-CRP, a significant association was observed in participants with higher hs-CRP levels [Q3 vs. Q1: HR 1.68 (1.06–2.65); Q4 vs. Q1: HR 1.80 (1.14–2.83)] (Pinteraction = 0.02). Moreover, similar results were observed for all-cause death and MACE, but no significance for stroke outcomes (Supplementary Table S1, available in www.besjournal.com).
Characteristics Quartile 1 Quartile 2 Quartile 3 Quartile 4 P for
interactionn, % HR (95% CI) n, % HR (95% CI) n, % HR (95% CI) n, % HR (95% CI) Gender Males 46 (3.1) Reference 69 (4.6) 1.19 (0.79–1.80) 96 (6.4) 1.46 (0.98–2.17) 116 (7.8) 1.91 (1.27–2.88) 0.01 Females 9 (1.7) Reference 6 (1.1) 2.16 (0.62–7.52) 18 (3.4) 0.98 (0.35–2.74) 29 (5.4) 1.21 (0.46–3.16) Age (years) < 65 37 (2.7) Reference 42 (3.0) 0.99 (0.61–1.62) 46 (3.3) 0.94 (0.58–1.51) 34 (2.5) 1.58 (0.95–2.63) 0.04 ≥ 65 18 (2.8) Reference 33 (5.1) 2.05 (1.01–4.13) 68 (10.5) 2.68 (1.37–5.22) 111 (17.1) 2.78 (1.43–5.40) hs-CRP (mg/dL) < 1.0 20 (2.2) Reference 29 (3.2) 1.29 (0.68–2.45) 42 (4.6) 1.16 (0.63–2.11) 45 (5.0) 1.84 (0.98–1.01) 0.02 ≥ 1.0 35 (3.1) Reference 46 (4.1) 1.34 (0.82–2.17) 72 (6.4) 1.68 (1.06–2.65) 100 (8.9) 1.80 (1.14–2.83) Note. Adjustments made for age, gender, body mass index (BMI), drinker status, smoking status, history of hypertension, hyperlipidemia, diabetes, and hs-CRP. Bold HR (95% CI) and P value indicate statistical significance. Lp-PLA2 = lipoprotein-associated phospholipase A2; HR = hazard ratio; CI = confidence interval; hs-CRP = high-sensitivity C-reactive protein. Table 3. Subgroup analyses of serum Lp-PLA2 associations with composite endpoints based on gender, age, and hs-CRP
Characteristics Quartile 1 Quartile 2 Quartile 3 Quartile 4 P for
interactionn, % HR
(95% CI)n, % HR
(95% CI)n, % HR
(95% CI)n, % HR
(95% CI)Stroke Gender Males 20 (1.3) Reference 26 (1.7) 1.41 (0.70–2.84) 37 (2.5) 1.57 (0.80–3.09) 28 (1.9) 1.98 (0.96–4.08) 0.36 Females 2 (0.4) Reference 4 (0.8) 5.65 (0.59–54.1) 8 (1.5) 2.00 (0.30–13.1) 12 (2.2) 5.68 (0.62–52.5) Age (years) < 65 16 (1.2) Reference 22 (1.6) 1.05 (0.50–2.19) 26 (1.9) 1.05 (0.52–2.13) 16 (1.2) 1.37 (0.58–3.25) 0.06 ≥ 65 6 (0.9) Reference 8 (1.2) 2.02 (0.39–12.6) 19 (2.9) 1.35 (0.20–9.04) 24 (3.7) 2.26 (0.42–12.1) hs-CRP (mg/dL) < 1.0 10 (1.1) Reference 11 (1.2) 2.95 (1.09–8.00) 20 (2.2) 1.42 (0.56–3.59) 15 (1.7) 2.86 (1.03–7.94) 0.07 ≥ 1.0 12 (1.1) Reference 19 (1.7) 2.19 (0.84–5.73) 25 (2.2) 2.19 (0.85–5.68) 25 (2.2) 2.64 (1.03–6.78) MACE Gender Males 27 (1.8) Reference 39 (2.6) 1.21 (0.70–2.09) 46 (3.1) 1.47 (0.85–2.57) 37 (2.5) 1.90 (1.05–3.44) 0.10 Females 4 (0.8) Reference 4 (0.8) 1.32 (0.25–7.01) 8 (1.5) 0.50 (0.11–2.33) 15 (2.8) 0.50 (0.10–2.66) Age (years) < 65 25 (1.8) Reference 33 (2.3) 1.05 (0.58–1.92) 29 (2.1) 0.98 (0.54–1.78) 20 (1.5) 1.16 (0.57–2.36) 0.05 ≥ 65 6 (0.9) Reference 11 (1.7) 2.32 (0.54–9.92) 25 (3.9) 3.19 (0.68–15.0) 32 (4.9) 4.31 (1.01–18.4) hs-CRP (mg/dL) < 1.0 13 (1.4) Reference 16 (1.8) 1.88 (0.79–4.46) 23 (2.5) 1.57 (0.70–3.53) 20 (2.2) 1.54 (0.67–3.54) 0.06 ≥ 1.0 18 (1.6) Reference 27 (2.4) 1.26 (0.62–2.58) 31 (2.8) 1.44 (0.68–3.08) 32 (2.9) 2.08 (0.98–4.40) All-cause death Gender Males 21 (1.4) Reference 35 (2.3) 1.46 (0.80–2.71) 56 (3.8) 1.67 (0.93–2.98) 93 (6.2) 2.26 (1.27–4.03) 0.04 Females 7 (1.3) Reference 2 (0.4) 3.99 (0.45–35.3) 10 (1.9) 1.84 (0.45–7.49) 17 (3.2) 1.78 (0.53–5.98) Age (years) < 65 15 (1.1) Reference 12 (0.9) 1.28 (0.49–3.30) 18 (1.3) 0.92 (0.40–2.15) 17 (1.2) 2.18 (0.88–5.37) 0.30 ≥ 65 13 (2.0) Reference 25 (3.9) 2.09 (0.95–4.60) 48 (7.4) 2.44 (1.15–5.16) 93 (14.4) 2.27 (1.10–4.70) hs-CRP (mg/dL) < 1.0 7 (0.8) Reference 14 (1.5) 1.46 (0.39–5.46) 22 (2.4) 1.09 (0.31–3.86) 30 (3.3) 2.05 (0.57–7.35) 0.08 ≥ 1.0 21 (1.9) Reference 23 (2.1) 1.64 (0.85–3.15) 44 (3.9) 2.02 (1.11–3.65) 80 (7.1) 2.13 (1.20–3.79) Note. Adjustments made for age, gender, body mass index (BMI), drinker status, smoking status, history of hypertension, hyperlipidemia, diabetes, and hs-CRP. Bold HR (95% CI) and P value indicate statistical significance. Table S1. Subgroup analyses of serum Lp-PLA2 associations with stroke, MACE, and all-cause death
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Participant Characteristics
Outcome Measures in Participant Groups of Lp-PLA2 during Follow-up
Association of Lp-PLA2 with Outcomes
Subgroup Analyses
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