262 Excitotoxicity, stroke
Prognostic value of serum lipoprotein(a) levels in patients with acute ischemic stroke Wei Zhanga and Xin-An Zhangb Inflammation plays a crucial role in the pathogenesis and prognosis of stroke. This study aims to investigate the relationship between acute ischemic stroke (AIS) and lipoprotein(a) [Lp(a)] levels and to determine the prognosis value of Lp(a) to predict the functional outcome. A total of 153 patients with AIS and 120 controls were included in the study. Serum Lp(a) levels were examined in both groups. Severity of the stroke was assessed using the National Institutes of Health Stroke Scale. The modified Rankin Scale scores at discharge were determined to establish the prognosis of stroke patients. The prognostic value of Lp(a) to predict the functional outcome within the time of discharge was analyzed by logistic regression analysis, after adjusting for the possible confounders. The results indicated that the serum Lp(a) levels were significantly higher in AIS patients as compared with normal controls [303 {interquartile range (IQR) 170–529 mg/l} and 144 (IQR 66–252 mg/l), respectively; P = 0.000]. In the 52 patients with an unfavorable functional outcome, serum Lp(a) levels were higher compared with those in patients with a favorable outcome [213 (IQR 143–347 mg/l) and
Introduction Stroke is a leading cause of mortality and subsequent serious long-term disability among survivors. Early detection and control of risk factors is thought to be crucial in reducing the risk of stroke and providing effective care. Rapidly measurable biomarkers to predict illness development, outcome, and mortality are pivotal for optimized care and allocation of healthcare resource [1]. Lipoprotein(a) [Lp(a)] is a genetic variant of low-density lipoprotein (LDL) that contains apolipoprotein(a), which is linked to the Apo B-100 through a disulfide bond that gives it great structural homology with plasminogen and confers its atherogenic and atherothrombotic properties [2]. Since the discovery of Lp(a) by Berg in 1963, increased Lp(a) concentrations have been found to be associated with a higher risk of cardiovascular disease in most studies [3]. High serum Lp(a) levels are now considered to be independent risk factors for cerebrovascular and cardiovascular atherosclerotic occlusive disease [4]. However, conflicting results have been reported [5]. Chakraborty et al. [6] found that high levels of Lp(a) are associated with increased severity and poorer long-term prognosis of stroke, and patients with admission levels of Lp(a) more than 77 mg/dl had increased mortality. In contrast, Hachinski et al. [7] and Unal et al. [8] found no relationship between ischemic stroke and Lp(a) levels. c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0959-4965
559 (IQR 357–845 mg/l), respectively; P = 0.000]. In multivariate analysis, there was an increased risk of unfavorable outcome associated with Lp(a) levels 300 mg/l or more (odds ratio 3.12; 95% confidence interval 1.55–5.28; P = 0.001) after adjusting for possible confounders. Serum Lp(a) can be considered as an independent short-term prognostic marker of functional outcome in Chinese patients with AIS even after correcting for possible confounding factors. NeuroReport c 2014 Wolters Kluwer Health | Lippincott 25:262–266 Williams & Wilkins. NeuroReport 2014, 25:262–266 Keywords: Chinese, lipoprotein(a), prognosis, stroke a
Department of Neurology, Shengjing Hospital of China Medical University and School of Kinesiology, Shenyang Sport University, Shenyang, China
b
Correspondence to Wei Zhang, No. 36, Sanhao Street, Heping District, Shenyang 110004, China Tel: + 86 24 8395 6319; fax: + 86 24 2483 8178; e-mail: [email protected] Received 2 September 2013 accepted 23 October 2013
To our knowledge, no study has evaluated Lp(a) as a prognostic marker after stroke in the Chinese population. The present study is an investigation of serum Lp(a) levels in acute ischemic stroke (AIS) patients during first-attack periods.
Patients and methods The study population comprised 153 consecutive patients with an AIS diagnosis, who had been referred to the Shengjing Hospital of China Medical University. Patients were diagnosed according to the WHO criteria [9] and with symptom onset within 24 h. Brain imaging (either computed tomography or MRI) was performed routinely within 24 h of admission. Exclusion criteria included blood not drawn within 24 h of hospital admission, malignant tumor, intracerebral hemorrhage, head trauma, severe edema, presence of diverse medical illness or current medications that influence serum Lp(a) levels, and incomplete workups for cerebrovascular status. The control cases (N = 100) were of similar age and sex distribution to the AIS patients. They had no known diseases and were not using any medication. A detailed medical history was taken and clinical and laboratory examinations were performed on all participants in both groups. The present study has been approved by the ethics committee of the Shengjing Hospital of China DOI: 10.1097/WNR.0000000000000094
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Prognostic value of serum Lp(a) levels Zhang and Zhang 263
Medical University. All participants were informed of the study protocol and their written informed consent was obtained according to the Declaration of Helsinki. At baseline, age, sex, and history of risk factors were obtained. Routine blood and biochemical tests and brain computed tomography/MRI scan were performed for all patients at admission. MRI with diffusion-weighted imaging was available for some patients. The lesion size was calculated using commonly used semiquantitative method. Lesions were ranked into three sizes: 1, small lesion with a volume of less than 10 ml; 2, medium lesion with a volume of 10–100 ml; and 3, large lesion with a volume of more than 100 ml [10]. The National Institutes of Health Stroke Scale (NIHSS) score was assessed on admission [11]. Functional outcome was obtained on discharge according to the modified Rankin Scale (mRS) score blinded to serum Lp(a) levels [12]. A favorable functional outcome was defined as a mRS score of 0–2 points, whereas an unfavorable functional outcome was defined as a mRS score of 3–6 points. The primary endpoint of this study was discharge. The secondary endpoint in stroke patients was death during hospital stay. Fasting venous blood was collected from all participants in vacutainer tubes and quickly centrifuged to avoid glycolysis. Serum samples were kept at – 801C until assay. Lp(a) levels were measured using immunoturbidimetric method by Olympus 2700 (Olympus, Tokyo, Japan). The lower detection limit was 40 mg/l and the line range was 40–1000 mg/l. The intra-assay coefficient of variation and interassay coefficient of variation were 1.1–1.5 and 1.3–1.8%, respectively. The median serum Lp(a) level in 100 healthy controls was 144 mg/l, which was similar to that in non-Hispanic Whites (120 mg/l) and lower than that of Blacks (390 mg/l) [13], and the 97.5 percentile was 398 mg/l. Results are expressed as percentages for categorical variables and as medians (interquartile ranges, IQRs) for the continuous variables. Values of the measured parameters were checked for normal distribution using the Kolmogorov–Smirnov test before statistical analysis. The Mann–Whitney U-test and w2-test were used to compare the two groups and the elevation ratios. Correlations among laboratory parameters were analyzed using Spearman’s rank correlation test. The influence of serum Lp(a) levels of 300 mg/l or more on functional outcome was assessed by logistic regression analysis, after adjusting for the following possible confounders: age; sex; alcohol abuse; smoking habit; hypertension; diabetes; atrial fibrillation; hyperlipoproteinemia; serum levels of white cells, triglycerides, cholesterol, high-density lipoprotein, LDL, D-dimer, fibrinogen, glucose, high-sensitivity C-reactive protein, and homocysteine; and NIHSS scores. Results were expressed as adjusted odds ratios (ORs) with the corresponding
95% confidence intervals (CIs). All statistical analyses were performed using SPSS for Windows (version 20.0; SPSS Inc., Chicago, Illinois, USA). Statistical significance was defined as P less than 0.05.
Results In our study, 153 patients with AIS were included and completed follow-up. The baseline characteristics of the 153 patients presenting with AIS are shown in Table 1. Overall, the median age was 62 years (IQR 55–72 years) and 42.5% were women. A total of 98 patients (64.1%) had a history of hypertension, 61 (39.9%) had hypercholesterolemia, 42 (27.5%) had diabetes mellitus, 39 (25.5%) had coronary heart disease, and 45 (29.4%) were diagnosed with atrial fibrillation. The median hospital stays was 21 days (IQR 12–32 days). The median NIHSS score on admission was 5 (IQR 3–7). An unfavorable functional outcome was found in 52 patients (34.0%) with a median mRS score of 4 (IQR 3–6). The results indicated that the serum Lp(a) levels were significantly higher in AIS patients compared with normal controls [303 (IQR 170–529 mg/l) and 144 (IQR 66–252 mg/l), respectively; P = 0.000]. In the subgroup of patients (n = 112) in whom MRI was available, Lp(a) levels paralleled lesion size (analysis of variance; P = 0.000). Median levels in patients with small, medium, and large lesions were 243 (IQR 110–390 mg/l), 356 (IQR 173–560 mg/l), 423 (IQR 299–697 mg/l), respectively. There was a positive correlation between serum Lp(a) levels and NIHSS score [r (Spearman’s) = 0.459; P = 0.000] (Fig. 1a). The relationship between serum Lp(a) level and mRS score was also found (r = 0.578, P = 0.000] (Fig. 1b). In addition, there was a modest correlation between serum Lp(a) levels and high-sensitivity C-reactive protein and LDL (r = 0.242, r = 0.203, respectively, P = 0.000). There was no correlation between serum Lp(a) levels and sex (P = 0.119) and age (P = 0.060). Serum levels of glucose, white blood cells, homocysteine, and high-density lipoprotein were not correlated with the serum Lp(a) levels (P > 0.05, respectively). In the 52 patients with an unfavorable functional outcome, serum Lp(a) levels were higher compared with those with a favorable outcome [213 (IQR 143–347 mg/l) and 559 (IQR 357–845 mg/l), respectively; P = 0.000] (Fig. 2). In the univariate model matched for sex and age, Lp(a) as a continuous variable was an independent predictor of unfavorable outcome, after adjusting for possible confounders (OR 1.005; 95% CI 1.001–1.009; P = 0.000). Further, in our study we found that an increased risk of unfavorable outcome was associated with Lp(a) levels of 300 mg/l or more (unadjusted OR 5.27; 95% CI 3.12–8.14; P = 0.000). This relationship was confirmed using the dose–response model. In multivariate analysis, there was an increased risk of unfavorable outcome associated with Lp(a) levels of 300 mg/l or more
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Table 1
Basal characteristic of patients with acute ischemic stroke
Characteristics N Female sex (n) Median age (IQR) (years) NIHSS score (IQR) mRS at discharge (IQR) Hospital stays (IQR) Cigarette smoking (%) Alcohol drinking (%) Hypertension (%) Diabetes at baseline (%) Hypercholesterolemia (%) Atrial fibrillation (%) Coronary heart disease (%) Family history of stroke (%) Laboratory findings Glucose (median, IQR) (mmol/l) White cell count (IQR) ( 109/l) Triglyceride (median, IQR) (mmol/l) Cholesterol (median, IQR) (mmol/l) HDL (median, IQR) (mmol/l) LDL (median, IQR) (mmol/l) Fibrinogen (median, IQR) (g/l) D-dimer (median, IQR) (mg/l) hs-CRP (median, IQR) (mg/dl) HCY (median, IQR) (mmol/l) Lp(a) (median, IQR) (mg/l)
62 5 2 21
6.0 7.2 1.7 4.56 0.94 3.26 3.4 286 1.24 14.16 303
All
Good outcome (mRS 0–2)
Poor outcome (mRS 3–6)
Pa
153 65 (55–72) (3–7) (1–3) (12–32) 29.4 24.8 64.1 27.5 39.9 29.4 25.5 22.9
101 40 (51–66) (2–4) (1–2) (11–29) 29.7 25.7 57.4 27.7 40.6 24.8 26.7 17.8
52 25 (60–78) (5–9) (3–5) (15–38) 28.8 23.1 76.9 26.9 38.5 38.5 28.8 32.7
NS 0.012 0.008 0.000 0.031 NS NS 0.029 NS NS 0.011 NS 0.009
(5.6–7.9) (5.5–9.2) (1.4–2.6) (4.04–5.05) (0.76–1.01) (2.67–3.77) (2.6–4.7) (210–378) (1.10–3.61) (11.50–19.93) (357–845)
0.021 0.038 NS NS 0.028 0.006 NS 0.018 0.002 0.004 0.000
(5.5–7.5) (5.4–8.6) (1.3–2.5) (4.04–4.99) (0.79–1.08) (2.58–3.64) (2.5–4.6) (185–337) (0.21–3.23) (10.61–17.88) (170–529)
58 3 1 17
5.6 7.0 1.6 4.43 1.02 3.11 3.3 245 1.13 11.57 213
66 6 4 25
(5.3–7.0) (4.9–8.2) (1.3–2.5) (3.92–4.89) (0.80–1.16) (2.41–3.51) (2.4–4.5) (170–309) (0.19–2.34) (11.36–16.82) (143–357)
6.2 7.6 1.7 4.59 0.84 3.38 3.4 313 2.16 15.69 559
HCY, homocysteine; HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; IQR, interquartile range; LDL, low-density lipoprotein; Lp(a), lipoprotein(a); mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale. a P value was assessed using Mann–Whitney U-test or w2-test.
Fig. 1
(b)
(a)
6 14
r(Spearman’s) = 0.578, P = 0.000
r(Spearman’s) = 0.459, P = 0.000 5
12
mRS score
NIHSS score
10 8 6
4
3
4 2 2 1
0 0.00
200.00
400.00
600.00 800.00 1000.00 1200.00 1400.00 Lp(a)(mg/l)
0.00
200.00
400.00
600.00 800.00 1000.00 1200.00 1400.00 Lp(a)(mg/l)
(a) The correction between serum lipoprotein(a) [Lp(a)] levels and the National Institutes of Health Stroke Scale (NIHSS) score; (b) the correction between serum Lp(a) levels and modified Rankin Scale (mRS) score.
(OR 3.12; 95% CI 1.55–5.28; P = 0.001) after adjusting for possible confounders (Table 2). In the subgroup of patients (n = 112) in whom MRI evaluations were performed, Lp(a) was found to be an independent outcome predictor with an OR of 3.32 (95% CI 1.64–5.41; P = 0.008) after adjusting for lesion size and the NIHSS score.
Discussions There is an accumulating evidence that emerging biological markers, including Lp(a), add to the prognostic value of conventional risk factors and may well serve as useful prognostic tools in identifying individuals at risk [14]. In this study, we first assessed serum Lp(a) levels with regard to their accuracy to predict functional
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Prognostic value of serum Lp(a) levels Zhang and Zhang 265
Fig. 2
1400.00
P = 0.000
1200.00
Lp(a)(mg/l)
1000.00 800.00 600.00 400.00 200.00 0.00 Favorable outcome (N = 101)
Unfavorable (N = 52)
Serum lipoprotein(a) [Lp(a)] levels in acute ischemic stroke patients with favorable and unfavorable outcome (Mann–Whitney U-test). All data are medians and interquartile ranges.
Serum lipoprotein(a) levels 300 mg/l or more as a prognostic marker to predict unfavorable outcome
Table 2
Unadjusted Adjusted for Adjusted for Adjusted for Adjusted for
model model model model
1 2 3 4
OR
95% CI
P
5.27 4.48 4.02 3.12 3.32
3.12–8.14 2.76–7.13 2.58–6.86 1.55–5.28 1.64–5.41
0.000 0.000 0.000 0.004 0.006
Model 1: adjusted for age, sex, alcohol abuse, smoking habit, and severity of stroke. Model 2: adjusted for age, sex, alcohol abuse, smoking habit, severity of stroke, hypertension, diabetes, atrial fibrillation, hyperlipoproteinemia, and family history of stroke. Model 3: adjusted for age, sex, alcohol abuse, smoking habit, severity of stroke, hypertension, diabetes, atrial fibrillation, hyperlipoproteinemia, and family history of stroke, and serum levels of triglyceride, cholesterol, high-density lipoprotein, low-density lipoprotein, D-dimer, fibrinogen, glucose, high-sensitivity C-reactive protein, and homocysteine. Model 4: adjusted for lesion size and the National Institutes of Health Stroke Scale score (N = 112). CI, confidence interval; OR, odds ratio.
outcome in patients with AIS within the time of discharge in the Chinese population. Our main finding was that Lp(a) can be considered as an independent short-term prognostic marker of functional outcome in Chinese patients with AIS even after correcting for possible confounding factors, and serum Lp(a) levels of 300 mg/l or more were associated with an 3.12-fold increase in unfavorable outcome. We also found that serum Lp(a) levels increased with infarct volume and neurological deficit (assessed by the NIHSS). In our study, we found that the serum Lp(a) levels were significantly higher in AIS patients compared with normal controls (P = 0.000). In contrast, Unal et al. [8] reported that there was no significant difference between Lp(a) levels in patients with AIS and controls (P = 0.150), whereas the results reported by Boden-Albala et al. [5]
were consistent with ours. Lp(a) levels in plasma vary widely among individuals and they are under strong genetic determination [15]. In addition, the variety of Lp(a) measurement methods used in studies and the sample size should also be considered. Serum inflammatory markers had been reported to be associated with recurrent vascular events [16], cognitive decline [17], long-term mortality [18], and short-tem outcomes [19]. Whiteley et al. [20] reported that elevated markers of acute inflammatory response after stroke are associated with poor outcomes. In our study, we found that serum Lp(a) levels 300 mg/l or more were associated with an 3.12-fold increase in unfavorable outcome. Similarly, Elkind et al. [21] reported that levels of LpPLA2 measured shortly after stroke predicted prognosis. In contrast, Woo et al. [22] showed no relationship between Lp(a), acute stroke severity, and prognosis in month 3 in their study in which patients were assessed using the Glasgow coma scale, and Unal et al. [8] supported those results. The inconformity needs to be further studied in population-based larger cohort studies. Whether the high serum Lp(a) is just an epiphenomenon to stroke severity or independently contributes to prognosis remains uncertain. A severe stroke per se implicates a poor outcome. However, there are several other reasons explaining unfavorable outcome in patients with higher Lp(a) levels. Lp(a) participates in the atherosclerotic process. It is possible that there is a contribution of Lp(a) in the atherosclerotic plaque formation, supported by an evidence showing that there is an accumulation of Lp(a) in the atherosclerotic lesions [23]. Next, by reason of the structural homology of apo(a) and plasminogen, Lp(a) might have a thrombogenic effect by its interference with intrinsic fibrinolysis [24].
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Lp(a) concentrations greater than 30 mg/dl are a frequent and independent risk factor for venous thrombosis [25]. Its prothrombotic effects may be ascribed to impaired fibrinolysis by inhibition of plasminogen activation rather than to amplification of platelet aggregation, which is shown to be reduced by Lp(a) in most cases. In addition, relationship between Lp(a) and endothelial dysfunction [26] and proinflammatory property of Lp(a) may be considered as additional explanations [27]. Some limitations of this observational study should be considered. First, without serial measurement of the circulating Lp(a) levels, this study yielded no data regarding when and how long Lp(a) is elevated in these patients. Second, Lp(a) measurements were recorded after the stroke and may not accurately reflect prestroke exposure. Finally, the effects of circulating Lp(a) on long-term clinical outcome were not included in the study protocol.
6
7 8
9 10
11
12 13
14
In summary, these data supported an association between serum Lp(a) levels and short-term prognosis in Chinese patients with AIS. We recommend that further studies should be carried out with respect to the mechanism between increased Lp(a) levels and poor outcome. If it is possible to elucidate this, the prognosis of Chinese patients with stroke might be improved.
Acknowledgements The authors are grateful to the Department of Neurology; the nurses, physicians, and patients who participated in our study; and the staff of the central laboratory of the Hospital.
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Conflicts of interest
There are no conflicts of interest.
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Prognostic value of serum lipoprotein(a) levels in patients with acute ischemic stroke Wei Zhanga and Xin-An Zhangb Inflammation plays a crucial role in the pathogenesis and prognosis of stroke. This study aims to investigate the relationship between acute ischemic stroke (AIS) and lipoprotein(a) [Lp(a)] levels and to determine the prognosis value of Lp(a) to predict the functional outcome. A total of 153 patients with AIS and 120 controls were included in the study. Serum Lp(a) levels were examined in both groups. Severity of the stroke was assessed using the National Institutes of Health Stroke Scale. The modified Rankin Scale scores at discharge were determined to establish the prognosis of stroke patients. The prognostic value of Lp(a) to predict the functional outcome within the time of discharge was analyzed by logistic regression analysis, after adjusting for the possible confounders. The results indicated that the serum Lp(a) levels were significantly higher in AIS patients as compared with normal controls [303 {interquartile range (IQR) 170–529 mg/l} and 144 (IQR 66–252 mg/l), respectively; P = 0.000]. In the 52 patients with an unfavorable functional outcome, serum Lp(a) levels were higher compared with those in patients with a favorable outcome [213 (IQR 143–347 mg/l) and
Introduction Stroke is a leading cause of mortality and subsequent serious long-term disability among survivors. Early detection and control of risk factors is thought to be crucial in reducing the risk of stroke and providing effective care. Rapidly measurable biomarkers to predict illness development, outcome, and mortality are pivotal for optimized care and allocation of healthcare resource [1]. Lipoprotein(a) [Lp(a)] is a genetic variant of low-density lipoprotein (LDL) that contains apolipoprotein(a), which is linked to the Apo B-100 through a disulfide bond that gives it great structural homology with plasminogen and confers its atherogenic and atherothrombotic properties [2]. Since the discovery of Lp(a) by Berg in 1963, increased Lp(a) concentrations have been found to be associated with a higher risk of cardiovascular disease in most studies [3]. High serum Lp(a) levels are now considered to be independent risk factors for cerebrovascular and cardiovascular atherosclerotic occlusive disease [4]. However, conflicting results have been reported [5]. Chakraborty et al. [6] found that high levels of Lp(a) are associated with increased severity and poorer long-term prognosis of stroke, and patients with admission levels of Lp(a) more than 77 mg/dl had increased mortality. In contrast, Hachinski et al. [7] and Unal et al. [8] found no relationship between ischemic stroke and Lp(a) levels. c 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins 0959-4965
559 (IQR 357–845 mg/l), respectively; P = 0.000]. In multivariate analysis, there was an increased risk of unfavorable outcome associated with Lp(a) levels 300 mg/l or more (odds ratio 3.12; 95% confidence interval 1.55–5.28; P = 0.001) after adjusting for possible confounders. Serum Lp(a) can be considered as an independent short-term prognostic marker of functional outcome in Chinese patients with AIS even after correcting for possible confounding factors. NeuroReport c 2014 Wolters Kluwer Health | Lippincott 25:262–266 Williams & Wilkins. NeuroReport 2014, 25:262–266 Keywords: Chinese, lipoprotein(a), prognosis, stroke a
Department of Neurology, Shengjing Hospital of China Medical University and School of Kinesiology, Shenyang Sport University, Shenyang, China
b
Correspondence to Wei Zhang, No. 36, Sanhao Street, Heping District, Shenyang 110004, China Tel: + 86 24 8395 6319; fax: + 86 24 2483 8178; e-mail: [email protected] Received 2 September 2013 accepted 23 October 2013
To our knowledge, no study has evaluated Lp(a) as a prognostic marker after stroke in the Chinese population. The present study is an investigation of serum Lp(a) levels in acute ischemic stroke (AIS) patients during first-attack periods.
Patients and methods The study population comprised 153 consecutive patients with an AIS diagnosis, who had been referred to the Shengjing Hospital of China Medical University. Patients were diagnosed according to the WHO criteria [9] and with symptom onset within 24 h. Brain imaging (either computed tomography or MRI) was performed routinely within 24 h of admission. Exclusion criteria included blood not drawn within 24 h of hospital admission, malignant tumor, intracerebral hemorrhage, head trauma, severe edema, presence of diverse medical illness or current medications that influence serum Lp(a) levels, and incomplete workups for cerebrovascular status. The control cases (N = 100) were of similar age and sex distribution to the AIS patients. They had no known diseases and were not using any medication. A detailed medical history was taken and clinical and laboratory examinations were performed on all participants in both groups. The present study has been approved by the ethics committee of the Shengjing Hospital of China DOI: 10.1097/WNR.0000000000000094
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Prognostic value of serum Lp(a) levels Zhang and Zhang 263
Medical University. All participants were informed of the study protocol and their written informed consent was obtained according to the Declaration of Helsinki. At baseline, age, sex, and history of risk factors were obtained. Routine blood and biochemical tests and brain computed tomography/MRI scan were performed for all patients at admission. MRI with diffusion-weighted imaging was available for some patients. The lesion size was calculated using commonly used semiquantitative method. Lesions were ranked into three sizes: 1, small lesion with a volume of less than 10 ml; 2, medium lesion with a volume of 10–100 ml; and 3, large lesion with a volume of more than 100 ml [10]. The National Institutes of Health Stroke Scale (NIHSS) score was assessed on admission [11]. Functional outcome was obtained on discharge according to the modified Rankin Scale (mRS) score blinded to serum Lp(a) levels [12]. A favorable functional outcome was defined as a mRS score of 0–2 points, whereas an unfavorable functional outcome was defined as a mRS score of 3–6 points. The primary endpoint of this study was discharge. The secondary endpoint in stroke patients was death during hospital stay. Fasting venous blood was collected from all participants in vacutainer tubes and quickly centrifuged to avoid glycolysis. Serum samples were kept at – 801C until assay. Lp(a) levels were measured using immunoturbidimetric method by Olympus 2700 (Olympus, Tokyo, Japan). The lower detection limit was 40 mg/l and the line range was 40–1000 mg/l. The intra-assay coefficient of variation and interassay coefficient of variation were 1.1–1.5 and 1.3–1.8%, respectively. The median serum Lp(a) level in 100 healthy controls was 144 mg/l, which was similar to that in non-Hispanic Whites (120 mg/l) and lower than that of Blacks (390 mg/l) [13], and the 97.5 percentile was 398 mg/l. Results are expressed as percentages for categorical variables and as medians (interquartile ranges, IQRs) for the continuous variables. Values of the measured parameters were checked for normal distribution using the Kolmogorov–Smirnov test before statistical analysis. The Mann–Whitney U-test and w2-test were used to compare the two groups and the elevation ratios. Correlations among laboratory parameters were analyzed using Spearman’s rank correlation test. The influence of serum Lp(a) levels of 300 mg/l or more on functional outcome was assessed by logistic regression analysis, after adjusting for the following possible confounders: age; sex; alcohol abuse; smoking habit; hypertension; diabetes; atrial fibrillation; hyperlipoproteinemia; serum levels of white cells, triglycerides, cholesterol, high-density lipoprotein, LDL, D-dimer, fibrinogen, glucose, high-sensitivity C-reactive protein, and homocysteine; and NIHSS scores. Results were expressed as adjusted odds ratios (ORs) with the corresponding
95% confidence intervals (CIs). All statistical analyses were performed using SPSS for Windows (version 20.0; SPSS Inc., Chicago, Illinois, USA). Statistical significance was defined as P less than 0.05.
Results In our study, 153 patients with AIS were included and completed follow-up. The baseline characteristics of the 153 patients presenting with AIS are shown in Table 1. Overall, the median age was 62 years (IQR 55–72 years) and 42.5% were women. A total of 98 patients (64.1%) had a history of hypertension, 61 (39.9%) had hypercholesterolemia, 42 (27.5%) had diabetes mellitus, 39 (25.5%) had coronary heart disease, and 45 (29.4%) were diagnosed with atrial fibrillation. The median hospital stays was 21 days (IQR 12–32 days). The median NIHSS score on admission was 5 (IQR 3–7). An unfavorable functional outcome was found in 52 patients (34.0%) with a median mRS score of 4 (IQR 3–6). The results indicated that the serum Lp(a) levels were significantly higher in AIS patients compared with normal controls [303 (IQR 170–529 mg/l) and 144 (IQR 66–252 mg/l), respectively; P = 0.000]. In the subgroup of patients (n = 112) in whom MRI was available, Lp(a) levels paralleled lesion size (analysis of variance; P = 0.000). Median levels in patients with small, medium, and large lesions were 243 (IQR 110–390 mg/l), 356 (IQR 173–560 mg/l), 423 (IQR 299–697 mg/l), respectively. There was a positive correlation between serum Lp(a) levels and NIHSS score [r (Spearman’s) = 0.459; P = 0.000] (Fig. 1a). The relationship between serum Lp(a) level and mRS score was also found (r = 0.578, P = 0.000] (Fig. 1b). In addition, there was a modest correlation between serum Lp(a) levels and high-sensitivity C-reactive protein and LDL (r = 0.242, r = 0.203, respectively, P = 0.000). There was no correlation between serum Lp(a) levels and sex (P = 0.119) and age (P = 0.060). Serum levels of glucose, white blood cells, homocysteine, and high-density lipoprotein were not correlated with the serum Lp(a) levels (P > 0.05, respectively). In the 52 patients with an unfavorable functional outcome, serum Lp(a) levels were higher compared with those with a favorable outcome [213 (IQR 143–347 mg/l) and 559 (IQR 357–845 mg/l), respectively; P = 0.000] (Fig. 2). In the univariate model matched for sex and age, Lp(a) as a continuous variable was an independent predictor of unfavorable outcome, after adjusting for possible confounders (OR 1.005; 95% CI 1.001–1.009; P = 0.000). Further, in our study we found that an increased risk of unfavorable outcome was associated with Lp(a) levels of 300 mg/l or more (unadjusted OR 5.27; 95% CI 3.12–8.14; P = 0.000). This relationship was confirmed using the dose–response model. In multivariate analysis, there was an increased risk of unfavorable outcome associated with Lp(a) levels of 300 mg/l or more
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Table 1
Basal characteristic of patients with acute ischemic stroke
Characteristics N Female sex (n) Median age (IQR) (years) NIHSS score (IQR) mRS at discharge (IQR) Hospital stays (IQR) Cigarette smoking (%) Alcohol drinking (%) Hypertension (%) Diabetes at baseline (%) Hypercholesterolemia (%) Atrial fibrillation (%) Coronary heart disease (%) Family history of stroke (%) Laboratory findings Glucose (median, IQR) (mmol/l) White cell count (IQR) ( 109/l) Triglyceride (median, IQR) (mmol/l) Cholesterol (median, IQR) (mmol/l) HDL (median, IQR) (mmol/l) LDL (median, IQR) (mmol/l) Fibrinogen (median, IQR) (g/l) D-dimer (median, IQR) (mg/l) hs-CRP (median, IQR) (mg/dl) HCY (median, IQR) (mmol/l) Lp(a) (median, IQR) (mg/l)
62 5 2 21
6.0 7.2 1.7 4.56 0.94 3.26 3.4 286 1.24 14.16 303
All
Good outcome (mRS 0–2)
Poor outcome (mRS 3–6)
Pa
153 65 (55–72) (3–7) (1–3) (12–32) 29.4 24.8 64.1 27.5 39.9 29.4 25.5 22.9
101 40 (51–66) (2–4) (1–2) (11–29) 29.7 25.7 57.4 27.7 40.6 24.8 26.7 17.8
52 25 (60–78) (5–9) (3–5) (15–38) 28.8 23.1 76.9 26.9 38.5 38.5 28.8 32.7
NS 0.012 0.008 0.000 0.031 NS NS 0.029 NS NS 0.011 NS 0.009
(5.6–7.9) (5.5–9.2) (1.4–2.6) (4.04–5.05) (0.76–1.01) (2.67–3.77) (2.6–4.7) (210–378) (1.10–3.61) (11.50–19.93) (357–845)
0.021 0.038 NS NS 0.028 0.006 NS 0.018 0.002 0.004 0.000
(5.5–7.5) (5.4–8.6) (1.3–2.5) (4.04–4.99) (0.79–1.08) (2.58–3.64) (2.5–4.6) (185–337) (0.21–3.23) (10.61–17.88) (170–529)
58 3 1 17
5.6 7.0 1.6 4.43 1.02 3.11 3.3 245 1.13 11.57 213
66 6 4 25
(5.3–7.0) (4.9–8.2) (1.3–2.5) (3.92–4.89) (0.80–1.16) (2.41–3.51) (2.4–4.5) (170–309) (0.19–2.34) (11.36–16.82) (143–357)
6.2 7.6 1.7 4.59 0.84 3.38 3.4 313 2.16 15.69 559
HCY, homocysteine; HDL, high-density lipoprotein; hs-CRP, high-sensitivity C-reactive protein; IQR, interquartile range; LDL, low-density lipoprotein; Lp(a), lipoprotein(a); mRS, modified Rankin Scale; NIHSS, National Institutes of Health Stroke Scale. a P value was assessed using Mann–Whitney U-test or w2-test.
Fig. 1
(b)
(a)
6 14
r(Spearman’s) = 0.578, P = 0.000
r(Spearman’s) = 0.459, P = 0.000 5
12
mRS score
NIHSS score
10 8 6
4
3
4 2 2 1
0 0.00
200.00
400.00
600.00 800.00 1000.00 1200.00 1400.00 Lp(a)(mg/l)
0.00
200.00
400.00
600.00 800.00 1000.00 1200.00 1400.00 Lp(a)(mg/l)
(a) The correction between serum lipoprotein(a) [Lp(a)] levels and the National Institutes of Health Stroke Scale (NIHSS) score; (b) the correction between serum Lp(a) levels and modified Rankin Scale (mRS) score.
(OR 3.12; 95% CI 1.55–5.28; P = 0.001) after adjusting for possible confounders (Table 2). In the subgroup of patients (n = 112) in whom MRI evaluations were performed, Lp(a) was found to be an independent outcome predictor with an OR of 3.32 (95% CI 1.64–5.41; P = 0.008) after adjusting for lesion size and the NIHSS score.
Discussions There is an accumulating evidence that emerging biological markers, including Lp(a), add to the prognostic value of conventional risk factors and may well serve as useful prognostic tools in identifying individuals at risk [14]. In this study, we first assessed serum Lp(a) levels with regard to their accuracy to predict functional
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Prognostic value of serum Lp(a) levels Zhang and Zhang 265
Fig. 2
1400.00
P = 0.000
1200.00
Lp(a)(mg/l)
1000.00 800.00 600.00 400.00 200.00 0.00 Favorable outcome (N = 101)
Unfavorable (N = 52)
Serum lipoprotein(a) [Lp(a)] levels in acute ischemic stroke patients with favorable and unfavorable outcome (Mann–Whitney U-test). All data are medians and interquartile ranges.
Serum lipoprotein(a) levels 300 mg/l or more as a prognostic marker to predict unfavorable outcome
Table 2
Unadjusted Adjusted for Adjusted for Adjusted for Adjusted for
model model model model
1 2 3 4
OR
95% CI
P
5.27 4.48 4.02 3.12 3.32
3.12–8.14 2.76–7.13 2.58–6.86 1.55–5.28 1.64–5.41
0.000 0.000 0.000 0.004 0.006
Model 1: adjusted for age, sex, alcohol abuse, smoking habit, and severity of stroke. Model 2: adjusted for age, sex, alcohol abuse, smoking habit, severity of stroke, hypertension, diabetes, atrial fibrillation, hyperlipoproteinemia, and family history of stroke. Model 3: adjusted for age, sex, alcohol abuse, smoking habit, severity of stroke, hypertension, diabetes, atrial fibrillation, hyperlipoproteinemia, and family history of stroke, and serum levels of triglyceride, cholesterol, high-density lipoprotein, low-density lipoprotein, D-dimer, fibrinogen, glucose, high-sensitivity C-reactive protein, and homocysteine. Model 4: adjusted for lesion size and the National Institutes of Health Stroke Scale score (N = 112). CI, confidence interval; OR, odds ratio.
outcome in patients with AIS within the time of discharge in the Chinese population. Our main finding was that Lp(a) can be considered as an independent short-term prognostic marker of functional outcome in Chinese patients with AIS even after correcting for possible confounding factors, and serum Lp(a) levels of 300 mg/l or more were associated with an 3.12-fold increase in unfavorable outcome. We also found that serum Lp(a) levels increased with infarct volume and neurological deficit (assessed by the NIHSS). In our study, we found that the serum Lp(a) levels were significantly higher in AIS patients compared with normal controls (P = 0.000). In contrast, Unal et al. [8] reported that there was no significant difference between Lp(a) levels in patients with AIS and controls (P = 0.150), whereas the results reported by Boden-Albala et al. [5]
were consistent with ours. Lp(a) levels in plasma vary widely among individuals and they are under strong genetic determination [15]. In addition, the variety of Lp(a) measurement methods used in studies and the sample size should also be considered. Serum inflammatory markers had been reported to be associated with recurrent vascular events [16], cognitive decline [17], long-term mortality [18], and short-tem outcomes [19]. Whiteley et al. [20] reported that elevated markers of acute inflammatory response after stroke are associated with poor outcomes. In our study, we found that serum Lp(a) levels 300 mg/l or more were associated with an 3.12-fold increase in unfavorable outcome. Similarly, Elkind et al. [21] reported that levels of LpPLA2 measured shortly after stroke predicted prognosis. In contrast, Woo et al. [22] showed no relationship between Lp(a), acute stroke severity, and prognosis in month 3 in their study in which patients were assessed using the Glasgow coma scale, and Unal et al. [8] supported those results. The inconformity needs to be further studied in population-based larger cohort studies. Whether the high serum Lp(a) is just an epiphenomenon to stroke severity or independently contributes to prognosis remains uncertain. A severe stroke per se implicates a poor outcome. However, there are several other reasons explaining unfavorable outcome in patients with higher Lp(a) levels. Lp(a) participates in the atherosclerotic process. It is possible that there is a contribution of Lp(a) in the atherosclerotic plaque formation, supported by an evidence showing that there is an accumulation of Lp(a) in the atherosclerotic lesions [23]. Next, by reason of the structural homology of apo(a) and plasminogen, Lp(a) might have a thrombogenic effect by its interference with intrinsic fibrinolysis [24].
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Lp(a) concentrations greater than 30 mg/dl are a frequent and independent risk factor for venous thrombosis [25]. Its prothrombotic effects may be ascribed to impaired fibrinolysis by inhibition of plasminogen activation rather than to amplification of platelet aggregation, which is shown to be reduced by Lp(a) in most cases. In addition, relationship between Lp(a) and endothelial dysfunction [26] and proinflammatory property of Lp(a) may be considered as additional explanations [27]. Some limitations of this observational study should be considered. First, without serial measurement of the circulating Lp(a) levels, this study yielded no data regarding when and how long Lp(a) is elevated in these patients. Second, Lp(a) measurements were recorded after the stroke and may not accurately reflect prestroke exposure. Finally, the effects of circulating Lp(a) on long-term clinical outcome were not included in the study protocol.
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14
In summary, these data supported an association between serum Lp(a) levels and short-term prognosis in Chinese patients with AIS. We recommend that further studies should be carried out with respect to the mechanism between increased Lp(a) levels and poor outcome. If it is possible to elucidate this, the prognosis of Chinese patients with stroke might be improved.
Acknowledgements The authors are grateful to the Department of Neurology; the nurses, physicians, and patients who participated in our study; and the staff of the central laboratory of the Hospital.
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Conflicts of interest
There are no conflicts of interest.
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