Heart Vessels DOI 10.1007/s00380-014-0514-7
ORIGINAL ARTICLE
Lipoprotein-associated phospholipase A2 is associated with postpartum hypertension in women with history of preeclampsia Yuheng Zhou • Jianmin Niu • Dongmei Duan Qiong Lei • Jiying Wen • Xiaohong Lin • Lijuan Lv • Longding Chen
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Received: 13 December 2013 / Accepted: 4 April 2014 Ó Springer Japan 2014
Abstract Both hypertension and preeclampsia (PE) are considered as inflammatory diseases. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory marker associated with lipid metabolism. We aimed to study the correlation and predictive value of Lp-PLA2 in postpartum hypertension after PE. A group of 160 PE patients (PE group) and a separate group of 160 normal pregnant women (control group) were recruited from January 2010 to October 2011. The average age in the PE group was 28.4 ± 4.5 years and the average gestational age was 34.7 ± 1.1 weeks. The average age in the control group was 27.8 ± 4.5 years and the average gestational age was 35.5 ± 1.2 weeks. General information (including age, gestational age, parity, history of metabolic disease, family history of high blood pressure, height, body weight before childbirth, and blood pressure) and blood samples were collected for measuring Lp-PLA2 and lipid parameters. From February to April in 2013, 153 cases in the PE group and 132 in the control group were re-called. We assessed their postpartum health, pregnancy, height, weight, and blood pressure. Serum mass of Lp-PLA2 in the PE group (210.67 ± 17.98 ng/mL) was significantly higher compared with that in the control group (174.72 ± 30.26 ng/mL) (P \ 0.01). The pro-gestation BMI, systolic blood pressure (SBP), diastolic blood pressure, total cholesterol, triglyceride, and low-density lipoprotein-cholesterol (LDL-C) were also significantly higher. Y. Zhou and J. Niu contributed equally to this work. Y. Zhou J. Niu (&) D. Duan Q. Lei J. Wen X. Lin L. Lv L. Chen Guangdong Women and Children Hospital, 13 Guang Yuan Xi Road, Guangzhou, Guangdong province 510010, People’s Republic of China e-mail: [email protected]
Correlation analysis showed that the level of Lp-PLA2 and SBP (r = 0.31), LDL-C (r = 0.37) were positively correlated. The incidence of postpartum hypertension in the PE group was higher than that in the normal control group. Logistic regression analysis showed that prenatal Lp-PLA2 mass was an independent risk factor for PE postpartum hypertension (OR 1.134,95 % CI 1.086–1.185). ROC curve analysis showed that the sensitivity of predicting postpartum hypertension was 73.2 % and the specific degree was 86.6 %, with Lp-PLA2 level of 217.75 ng/mL for boundary value. The onset of postpartum hypertension in PE patients may contribute to vascular inflammation, which is associated with antepartum lipid metabolism. Keywords Preeclampsia Dyslipidemia Vascular inflammation Hypertension Lp-PLA2
Introduction According to the World Health Organization, the prevalence of hypertension in females was about 24.8 % in 2012 [1]. High blood pressure is taken seriously, not only because of its high incidence but also because it is a major risk factor for cardiovascular disease (CVD) and kidney disease [2]. However, the pathogenesis is still outstanding. Inflammation has been found to be involved in the development of hypertension. Preeclampsia (PE) is defined as the onset of high blood pressure and proteinuria after 20 weeks of gestation and is characterized by multiple organ involvement [3]. Studies suggest that women with history of PE are at a higher risk of developing hypertension postpartum [4, 5]. Inflammation also has an important role in the pathogenesis of PE, with some scholars even considering PE as
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a kind of inflammatory disease. Dyslipidemia is one of the important causes of PE that leads to excessive inflammation. Coincidentally, patients with PE often exhibit excessive dyslipidemia and low-grade inflammation. However, whether these pathological changes influence the occurrence of hypertension in the future or not remains inconclusive. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme and inflammatory marker associated with lipid metabolism. Lp-PLA2 is a 45-kDa protein with 441 amino acid residues. It is calcium independent and is produced and secreted by monocytes, macrophages, and platelets [6, 7]. This enzyme catalyzes the oxidation of free fatty acid (oxFFA) and lysolecithin (lyso-PC) by hydrolysis of lecithin, which functions in inflammatory promotion. OxFFA can increase oxidative stress directly or indirectly and increase the level of oxidative lowdensity lipoproteins (oxLDL). In addition, lyso-PC is associated with production of inflammatory cytokines and promotion of adhesion molecule and cytokine expression. Subsequently, macrophages are stimulated to migrate into vascular smooth muscles. Lyso-PC can also increase the level of Lp-PLA2, which eventually aggravates the degree of inflammation. Different from classic inflammatory markers (such as C-reactive protein, PAPP), about 80 % of Lp-PLA2 normally combines with LDL-C. The remaining 20 % merge with HDL-C [8–10]. All of the foregoing are expressed in vascular inflammation lesions, so the expression of Lp-PLA2 is actually a marker that reflects vascular inflammation associated with lipid metabolism. Our objective was to discuss the relationship among vascular inflammation, lipid metabolism, and hypertension. We aimed to measure the levels of Lp-PLA2 and lipid parameters [total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and lowdensity lipoprotein cholesterol (LDL-C)] in women with PE and in normal women antepartum. We also evaluated the prevalence of hypertension postpartum.
Methods
control group, which shared almost the same condition as the 160 PE patients. Their average age was 27.8 ± 4.5 years and the average gestational age was 35.5 ± 1.2 weeks. All research subjects signed the medical informed consent, and their general information (including age, gestational age, parity, history of metabolic disease, family history of high blood pressure, height, progestational body weight, and blood pressure) were well registered. Blood samples were also collected. From February to April in 2013, we re-called the patients, including 153 from the PE group (with an average duration of postpartum of 2.4 ± 0.3 years) and 132 from the normal control group (with an average duration of postpartum of 2.4 ± 0.4 years). PE required that hypertension was at SBP [140 mmHg or DBP [90 mmHg, presenting beyond 20th week of gestation with [300 mg protein in a 24-h urine collection or [30 mg/mmol in a spot urine sample [11]. Women in the control group were recruited for normotension and health during pregnancy. The study was approved by the local hospital Ethics Committee, with all recruits informed before the initiation of the study. Baseline examinations Blood pressure Blood pressure was taken twice with the same mercury sphygmomanometer after 5 min at supine position under a state of rest. When abnormal BP (SBP[140 mmHg and/or DBP [90 mmHg) was found, the participant was re-called for a recheck in the next 2 days for BP diagnosis. According to NICE guidance in 2011 [12], normotension is defined as SBP \120 mmHg and DBP \80 mmHg. Hypertension is present if SBP [140 mmHg or DBP [90 mmHg. Analysis of lipid profile All participants underwent fasting for 8–12 h prior to blood sample collection the following morning. The concentrations of TC, TG, HDL-C, and LDL-C were measured using an automatic biochemical system (Advia 1650 Chemistry System, Siemens, Munich, Germany).
Subjects Lp-PLA2 assay Up to 320 participants (160 PE cases and 160 normal pregnant women) were recruited from the department of obstetrics of Guangdong Women and Children Hospital. The recruits comprised PE patients who underwent treatment and gave birth from January 2010 to October 2011. Their average age was 28.4 ± 4.5 years and their average gestational age was 34.7 ± 1.1 weeks. Among the 320 subjects, 160 were normal pregnant women designated as
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Blood (4 ml) was collected in a coagulation-promoting tube and preserved under 22–25 °C for 2 h and centrifuged immediately for 20 min at 1500 rpm for serum separation. Serum samples were cryopreserved at –80 °C until the time of Lp-PLA2 assay. Serum level of Lp-PLA2 was measured using an enzyme-linked immunosorbent assay (PLAC Test, diaDexus, Inc. South San Francisco, CA, USA). Following
Heart Vessels Table 1 Comparison of general information and laboratory parameters
PE (n = 153) Mean ± SD
r (P value)
Mean ± SD
P value r (P value)
Age, years
28.4 ± 4.7
0.002 (0.982)
27.4 ± 4.5
0.009 (0.923)
0.089
Parity, times
1.41 ± 0.6
0.045 (0.13)
1.46 ± 0.7
0.08 (0.74)
0.454
P-BMI, kg/m2 SBP, mmHg
Lp-PLA2 lipoprotein-associated phospholipase A2, P-BMI progestational body mass index
Control (n = 132)
22 ± 3.3 154.9 ± 16.1
0.13 (0.117)
20.2 ± 1.8
0.09 (0.291)
\0.001
0.31 (0.032)
112.6 ± 10.4
0.12 (0.163)
\0.001 \0.001
DBP, mmHg
97.6 ± 11.7
0.12 (0.119)
68.7 ± 7.6
0.05 (0.581)
TC, mmol/L
6.13 ± 1.38
0.08 (0.351)
5.83 ± 1.16
0.16 (0.66)
TG, mmol/L
3.57 ± 1.48
0.13 (0.72)
2.85 ± 1.31
0.12 (0.153)
0.049 \0.001
LDL-C, mmol/L
3.14 ± 0.82
0.37 (\ 0.001)
2.83 ± 0.67
0.59 (\ 0.001)
0.001
HDL-C, mmol/L
2.09 ± 0.63
0.17 (0.403)
2.14 ± 0.38
0.08 (0.352)
0.34
Lp-PLA2, ng/ml
210.67 ± 17.98
–
174.72 ± 30.26
–
\0.001
the protocol described by Emmanouil [13], samples were incubated in microtiter plate wells with immobilized monoclonal antibody (2C10) against Lp-PLA2. The enzyme was identified by a second monoclonal anti-LpPLA2 antibody (4B4) labeled with horseradish peroxidase. The standard used was recombinant Lp-PLA2. The average CV was 5.62 %, with no cross-reactivity with other A2 phospholipases. Analyses of all the samples, standards, and controls were run in duplicate.
5.83 ± 1.16) mmol/L, TG (3.57 ± 1.48 vs. 2.85 ± 1.31) mmol/L, LDL-C (3.14 ± 0.82 vs. 2.83 ± 0.67) mmol/L, and Lp-PLA2 mass (210.67 ± 17.98 vs. 174.72 ± 30.26) ng/ml were significantly higher (P \ 0.05) in PE group than those in the control. There were no significant difference in the average of age (28.4 ± 4.7 vs. 27.4 ± 4.5) year-old, parity (1.41 ± 0.6 vs. 1.46 ± 0.7) times, HDL-C (2.09 ± 0.63 vs. 2.14 ± 0.38) mmol/L (P [ 0.05) (Table 1).
Statistical analysis
Correlation between Lp-PLA2 and A-BMI, BP and Lipid parameters
Statistical analyses were performed using the Statistical Program for Social Sciences (SPSS) software for Windows, version 20.0 (Chicago, IL). Chi square test was used to compare the prevalence of hypertension and normotension in PE and Control group. Differences of parameters were analyzed by using the independent-sample t test or the Mann–Whitney U test as appropriate. Results were presented as mean ± SD. Relationship between Lp-PLA2 and other variables was evaluated by using Spearman’s correlation analysis. Binary logistic regression analysis was used with BP as the dependent variable. P \ 0.05 was considered statistically significant. ROC curve analysis was used to evaluate the predicted value of hypertension risk with Lp-PLA2 in PE patients.
Result
Spearman’s correlation analysis using Lp-PLA2 as the dependent variable and P-BMI, BP(SBP and DBP) and lipid profiles as independent variables showed that serum level of Lp-PLA2 positively correlated with SBP (r = 0.31, P = 0.03) and LDL-C (r = 0.37, P \ 0.01) in PE group. In control group, it is positively correlated with LDL-C (r = 0.59, P \ 0.01) (Table 1). The situation of postpartum follow-up From February to April in 2013, 153 cases in the PE group and 132 in the control group were re-called. The average of follow-up time in PE Group is 2.4 ± 0.3 years (the longest is 3.1 years, while the shortest is 1.5 years). Within the control group, the average is 2.4 ± 0.4 years (the longest is 3.0 years, while the shortest is 1.4 years). No significant difference was showed between the two groups.
Comparison of general information and lipid parameters and Lp-PLA2 mass
The incidence of hypertension
Pro-gestation BMI (22 ± 3.3 vs 20.2 ± 1.8) kg/m2, SBP (154.9 ± 16.1 vs. 112.6 ± 10.4) mmHg, DBP (97.6 ± 11.7 vs. 68.7 ± 7.6) mmHg, TC (6.13 ± 1.38 vs.
The incidence of postpartum hypertension in the PE group was 16.83 %, which was higher than that in the normal control group (1.01 %, P \ 0.001).
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Heart Vessels Fig. 1 Receiver operating characteristic (ROC) curves for pro-gestational BMI, SBP, DBP and laboratory parameters in women with hypertension in PE group
Binary logistic analysis between postpartum hypertension and prenatal factors We supposed the occurrence of postpartum hypertension as dependent variable. TC, TG, HDL-C, LDL-C, and LpPLA2 were regarded as independent variables. The results showed that postpartum hypertension is correlated to LpPLA2(OR 1.134, 95 % CI 1.086–1.185, P \ 0.05), HDL-C (OR 1.698, 95 % CI 0.997–2.891, P = 0.005), and LDL-C (OR 0.43, 95 % CI 0.209–0.886, P = 0.022). After adjusting other factors, it indicated that Lp-PLA2 mass was an independent risk factor for PE postpartum hypertension (OR 1.134,95 % CI 1.086–1.185).
The predicted value of hypertension risk with Lp-PLA2 in PE The area under the ROC curves was 0.882 (95 % CI 0.82–0.92) for postpartum hypertension. The sensitivity of predicting postpartum hypertension was 73.2 % and the specific degree was 86.6 %, with Lp-PLA2 level of 217.75 ng/mL for boundary value. The areas of progestational BMI (0.54, 95 % CI 0.46–0.62), SBP (0.61, 95 % CI 0.53–0.69), DBP (0.57, 95 % CI 0.49–0.65), TC (0.52, 95 % CI 0.43–0.61), TG (0.54, 95 % CI 0.46–0.62), HDL-C (0.58, 95 % CI 0.5–0.66), and LDL-C (0.58, 95 % CI 0.5–0.66) were totally lower than 0.7, which means with little predicting value. (Fig. 1)
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Discussion Relation between Lp-PLA2 and postpartum hypertension Compared with normal pregnant women, women in PE group had significantly higher levels of TC, TG, and LDLC, but lower HDL-C. These results demonstrated that PE exists in abnormal lipid metabolism during pregnancy. Logistic analysis suggested that LDL-C and HDL-C were independent risk factors for postpartum hypertension, indicating prenatal lipid metabolism was indeed linked with postpartum hypertension. To meet the needs of maternal and fetal growth and development in normal pregnancy, lipid metabolism is relatively higher than in progestation stages. However, this condition is much more severe in PE. Clausen et al. [14] found that hypertriglyceridemia appearing before the 20th week of gestation was associated with early onset of PE. Compared with normal pregnant women, TG concentration in PE patients is significantly elevated. Increasing oxidative stress is linked to a direct damage to endothelial cells and stimulates endothelial adhesion molecule (as VCAM-1) and coagulation factor (PAI–1) expression [15, 16]. The inflammatory cells combine, thereby expanding the endothelial inflammation. Elevated TG also has a tendency to accumulate in blood vessels (e.g., uterine spiral artery), impairing endothelial tissues by producing small and dense LDL directly or indirectly. The accumulation of LDL in blood vessel walls can be oxidized to oxLDL [17]. The
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latter activates the receptor LOX-1 to promote adhesion molecule genes (MCP-1, ICAM-1, VCAM-1, P-select element and so on) and ultimately induces inflammatory cells to adhere to blood vessel walls. The endothelial cells take in LOX-1, leading to endothelial dysfunction with the destruction of endothelial integrity or even secretion disorder, thus forming endothelial injury. Hypercholesterolemia participates in endothelial damage in PE by lipid peroxidation [18]. Lipid peroxide and free radicals produced by lipid oxidation damage vascular endothelial tissues directly and prompt platelet adhesion and aggregation. Moreover, irregular blood pressure appears, symptomatic of a series of pathological changes of vasospasm contractions that leads to the occurrence of PE [18]. Similar to the mechanisms mentioned above, dyslipidemia also promotes the development of hypertension by inducing inflammation and oxidative stress. Previous studies suggest that the rise of TG and LDL and the decline of HDL can increase the risk of hypertension [19–22]. Animal studies have proven that chronic low-grade inflammation status in renal tubules is closely related to high blood pressure. For example, in all hypertension animal models, T lymphocytes and macrophages invade the renal tubules–interstitial cells. Renal interstitial inflammation in hypertension is always accompanied by invasion of inflammatory cells and reactive oxygen species (ROS) and angiotensin II produced by kidney cells. Low-grade inflammation of the renal tubules can induce high blood pressure in mice. At the same time, high blood pressure itself can increase chemical factors and adhesion molecules by oxidative stress to promote inflammatory response and further remodeling of vascular structures [23]. Clinical studies have also found that inflammatory mediators increase in patients with high blood pressure. An 11-year follow-up study [24] found that the men whose basic level of c-reactive protein (CRP) were higher than 3.0 mg/L were at higher risk of developing hypertension in the future compared with men whose CRP were lower than 1.0 mg/L. Sesso et al. [25] found that women with higher levels of CRP had higher risk of hypertension compared with those with lower CRP levels. A retrospective study [26] found that increase in plasma fibrinogen, a1-antitrypsin, haptoglobin, ceruloplasmin, and orosomucoid in individuals can lead to elevated blood pressure in the future. Spaan et al. [27] found that the onset of hypertension was linked with obesity, higher fasting insulin, low-density lipoprotein, albuminuria, and delivery time. Further analysis found that an increase in the components of the metabolic patterns (blood pressure, glucose and lipids) will likely increase the risk of hypertension. Thus, glucose and lipid metabolic abnormalities may promote postpartum hypertension. However, in our ROC curve analysis, lipid metabolism was not found to have a prediction of
postpartum hypertension in the future, implying that a different mechanism is involved in lipid metabolism and hypertension. We found a significant increase in the PE group of prenatal Lp-PLA2 with the changes linked to LDL. Furthermore, an increase in Lp-PLA2 expression may increase the risk of postpartum hypertension. Our study suggested that abnormal lipid metabolism during gestation may increase the risk of hypertension in the future by promoting vascular inflammation. Lavi ea al. [28] found that the level of Lp-PLA2 in circulation was associated with coronary endothelial function. Early atherosclerosis was detected in patients through three-dimensional vascular remodeling. The atherosclerosis degree was determined by the amount of LpPLA2, as well as by the increase in the levels of lyso-PC. Lyso-PC is one of the products of Lp-PLA2 from hydrolysis of phospholipids, which is linked to oxidative stress. Lyso-PC formation is one of the mechanisms that induce atherosclerosis. Thus, Lp-PLA2 is an inflammation marker related to oxidative stress, it is also involved in endothelial injuries. We also found that Lp-PLA2 was related to prenatal systolic blood pressure levels. High blood pressure can lead to significant increase in shear force of vascular blood flow (turbulent formation), causing arterial injuries. Adhesion molecules expressed by impaired endothelial cell promote aggregation of white blood cells in the subcutaneous tissue. White blood cells produce interleukin, cytokines, and active oxygen-free radicals, which eventually lead to abnormal inflammatory response in the arterial walls [29, 30]. Overall, PE patients showed a certain degree of vascular inflammation, which is not only related to the severity of the disease but may also be involved in the onset of hypertension in the future. Predictive value of Lp-PLA2 in hypertension In this study, we found that Lp-PLA2 had a negative predictive value in postpartum hypertension of PE. Nguyen et al. [31] found that BMI has a predictive role in hypertension, in which women’s ROC area was 0.62 (95 % CI: 0.58–0.65). After age adjustment, the ROC area was 0.71 (95 % CI: 0.68–0.74). The highest sensitivity and specific degree was 23.5 kg/m2. Kuklinska et al. [32] found that biomarkers of oxidative stress and endothelial injury also have predictive effects for hypertension, with prostaglandins (ROC area of 0.647) as the most profound. Lp-PLA2 is a biomarker that is linked to lipid metabolism and may reflect the state of endothelial damage of vascular inflammation. Thus, Lp-PLA2 detection may lead to a possible higher predictive value in hypertension.
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Prospects The onset of postpartum hypertension in PE patients may contribute to vascular inflammation, which is associated with antepartum lipid metabolism. Furthermore, vascular inflammation has an important function in the formation of atherosclerosis (AS) and cardiovascular disease (CVD). Kajiya et al. [33] reported that serum adipocyte fatty acidblinding protein (A-FABP) might be involved in coronary plaque vulnerability by its critical role in the development of AS by organizing macrophage cholesterol trafficking and inflammation. Similarly, Lp-PLA2 is also one of predictive inflammatory markers of cardiovascular risk. The most important expectation of our study is whether LpPLA2 can use to decrease CVD risk for women with PE history. As PE had been considered as a CVD risk factor for females [34], Lp-PLA2 should be detected not only to predict hypertension, but also to ascertain information relating other CVDs and Lp-PLA2. Lipid-lowering treatment may be an effective action for this expectation. For example, Ezetimibe is a lipid-lowering drug that can efficiently decreases LDL-C and may have an important role in preventing AS by its lipid-lowering and anti-inflammatory effect [35]. It had been reported that Ezetimibe could significantly decrease total plasma Lp-PLA2 mass [36]. All of these are need further studies including long-time follow-up for PE patient and even the adverse effects of lipidlowering drug on pregnant women. Acknowledgment This study was supported by a grant from Guangdong Science and Technology Department, Fund Code: 2011B31800264.
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ORIGINAL ARTICLE
Lipoprotein-associated phospholipase A2 is associated with postpartum hypertension in women with history of preeclampsia Yuheng Zhou • Jianmin Niu • Dongmei Duan Qiong Lei • Jiying Wen • Xiaohong Lin • Lijuan Lv • Longding Chen
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Received: 13 December 2013 / Accepted: 4 April 2014 Ó Springer Japan 2014
Abstract Both hypertension and preeclampsia (PE) are considered as inflammatory diseases. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an inflammatory marker associated with lipid metabolism. We aimed to study the correlation and predictive value of Lp-PLA2 in postpartum hypertension after PE. A group of 160 PE patients (PE group) and a separate group of 160 normal pregnant women (control group) were recruited from January 2010 to October 2011. The average age in the PE group was 28.4 ± 4.5 years and the average gestational age was 34.7 ± 1.1 weeks. The average age in the control group was 27.8 ± 4.5 years and the average gestational age was 35.5 ± 1.2 weeks. General information (including age, gestational age, parity, history of metabolic disease, family history of high blood pressure, height, body weight before childbirth, and blood pressure) and blood samples were collected for measuring Lp-PLA2 and lipid parameters. From February to April in 2013, 153 cases in the PE group and 132 in the control group were re-called. We assessed their postpartum health, pregnancy, height, weight, and blood pressure. Serum mass of Lp-PLA2 in the PE group (210.67 ± 17.98 ng/mL) was significantly higher compared with that in the control group (174.72 ± 30.26 ng/mL) (P \ 0.01). The pro-gestation BMI, systolic blood pressure (SBP), diastolic blood pressure, total cholesterol, triglyceride, and low-density lipoprotein-cholesterol (LDL-C) were also significantly higher. Y. Zhou and J. Niu contributed equally to this work. Y. Zhou J. Niu (&) D. Duan Q. Lei J. Wen X. Lin L. Lv L. Chen Guangdong Women and Children Hospital, 13 Guang Yuan Xi Road, Guangzhou, Guangdong province 510010, People’s Republic of China e-mail: [email protected]
Correlation analysis showed that the level of Lp-PLA2 and SBP (r = 0.31), LDL-C (r = 0.37) were positively correlated. The incidence of postpartum hypertension in the PE group was higher than that in the normal control group. Logistic regression analysis showed that prenatal Lp-PLA2 mass was an independent risk factor for PE postpartum hypertension (OR 1.134,95 % CI 1.086–1.185). ROC curve analysis showed that the sensitivity of predicting postpartum hypertension was 73.2 % and the specific degree was 86.6 %, with Lp-PLA2 level of 217.75 ng/mL for boundary value. The onset of postpartum hypertension in PE patients may contribute to vascular inflammation, which is associated with antepartum lipid metabolism. Keywords Preeclampsia Dyslipidemia Vascular inflammation Hypertension Lp-PLA2
Introduction According to the World Health Organization, the prevalence of hypertension in females was about 24.8 % in 2012 [1]. High blood pressure is taken seriously, not only because of its high incidence but also because it is a major risk factor for cardiovascular disease (CVD) and kidney disease [2]. However, the pathogenesis is still outstanding. Inflammation has been found to be involved in the development of hypertension. Preeclampsia (PE) is defined as the onset of high blood pressure and proteinuria after 20 weeks of gestation and is characterized by multiple organ involvement [3]. Studies suggest that women with history of PE are at a higher risk of developing hypertension postpartum [4, 5]. Inflammation also has an important role in the pathogenesis of PE, with some scholars even considering PE as
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a kind of inflammatory disease. Dyslipidemia is one of the important causes of PE that leads to excessive inflammation. Coincidentally, patients with PE often exhibit excessive dyslipidemia and low-grade inflammation. However, whether these pathological changes influence the occurrence of hypertension in the future or not remains inconclusive. Lipoprotein-associated phospholipase A2 (Lp-PLA2) is an enzyme and inflammatory marker associated with lipid metabolism. Lp-PLA2 is a 45-kDa protein with 441 amino acid residues. It is calcium independent and is produced and secreted by monocytes, macrophages, and platelets [6, 7]. This enzyme catalyzes the oxidation of free fatty acid (oxFFA) and lysolecithin (lyso-PC) by hydrolysis of lecithin, which functions in inflammatory promotion. OxFFA can increase oxidative stress directly or indirectly and increase the level of oxidative lowdensity lipoproteins (oxLDL). In addition, lyso-PC is associated with production of inflammatory cytokines and promotion of adhesion molecule and cytokine expression. Subsequently, macrophages are stimulated to migrate into vascular smooth muscles. Lyso-PC can also increase the level of Lp-PLA2, which eventually aggravates the degree of inflammation. Different from classic inflammatory markers (such as C-reactive protein, PAPP), about 80 % of Lp-PLA2 normally combines with LDL-C. The remaining 20 % merge with HDL-C [8–10]. All of the foregoing are expressed in vascular inflammation lesions, so the expression of Lp-PLA2 is actually a marker that reflects vascular inflammation associated with lipid metabolism. Our objective was to discuss the relationship among vascular inflammation, lipid metabolism, and hypertension. We aimed to measure the levels of Lp-PLA2 and lipid parameters [total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and lowdensity lipoprotein cholesterol (LDL-C)] in women with PE and in normal women antepartum. We also evaluated the prevalence of hypertension postpartum.
Methods
control group, which shared almost the same condition as the 160 PE patients. Their average age was 27.8 ± 4.5 years and the average gestational age was 35.5 ± 1.2 weeks. All research subjects signed the medical informed consent, and their general information (including age, gestational age, parity, history of metabolic disease, family history of high blood pressure, height, progestational body weight, and blood pressure) were well registered. Blood samples were also collected. From February to April in 2013, we re-called the patients, including 153 from the PE group (with an average duration of postpartum of 2.4 ± 0.3 years) and 132 from the normal control group (with an average duration of postpartum of 2.4 ± 0.4 years). PE required that hypertension was at SBP [140 mmHg or DBP [90 mmHg, presenting beyond 20th week of gestation with [300 mg protein in a 24-h urine collection or [30 mg/mmol in a spot urine sample [11]. Women in the control group were recruited for normotension and health during pregnancy. The study was approved by the local hospital Ethics Committee, with all recruits informed before the initiation of the study. Baseline examinations Blood pressure Blood pressure was taken twice with the same mercury sphygmomanometer after 5 min at supine position under a state of rest. When abnormal BP (SBP[140 mmHg and/or DBP [90 mmHg) was found, the participant was re-called for a recheck in the next 2 days for BP diagnosis. According to NICE guidance in 2011 [12], normotension is defined as SBP \120 mmHg and DBP \80 mmHg. Hypertension is present if SBP [140 mmHg or DBP [90 mmHg. Analysis of lipid profile All participants underwent fasting for 8–12 h prior to blood sample collection the following morning. The concentrations of TC, TG, HDL-C, and LDL-C were measured using an automatic biochemical system (Advia 1650 Chemistry System, Siemens, Munich, Germany).
Subjects Lp-PLA2 assay Up to 320 participants (160 PE cases and 160 normal pregnant women) were recruited from the department of obstetrics of Guangdong Women and Children Hospital. The recruits comprised PE patients who underwent treatment and gave birth from January 2010 to October 2011. Their average age was 28.4 ± 4.5 years and their average gestational age was 34.7 ± 1.1 weeks. Among the 320 subjects, 160 were normal pregnant women designated as
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Blood (4 ml) was collected in a coagulation-promoting tube and preserved under 22–25 °C for 2 h and centrifuged immediately for 20 min at 1500 rpm for serum separation. Serum samples were cryopreserved at –80 °C until the time of Lp-PLA2 assay. Serum level of Lp-PLA2 was measured using an enzyme-linked immunosorbent assay (PLAC Test, diaDexus, Inc. South San Francisco, CA, USA). Following
Heart Vessels Table 1 Comparison of general information and laboratory parameters
PE (n = 153) Mean ± SD
r (P value)
Mean ± SD
P value r (P value)
Age, years
28.4 ± 4.7
0.002 (0.982)
27.4 ± 4.5
0.009 (0.923)
0.089
Parity, times
1.41 ± 0.6
0.045 (0.13)
1.46 ± 0.7
0.08 (0.74)
0.454
P-BMI, kg/m2 SBP, mmHg
Lp-PLA2 lipoprotein-associated phospholipase A2, P-BMI progestational body mass index
Control (n = 132)
22 ± 3.3 154.9 ± 16.1
0.13 (0.117)
20.2 ± 1.8
0.09 (0.291)
\0.001
0.31 (0.032)
112.6 ± 10.4
0.12 (0.163)
\0.001 \0.001
DBP, mmHg
97.6 ± 11.7
0.12 (0.119)
68.7 ± 7.6
0.05 (0.581)
TC, mmol/L
6.13 ± 1.38
0.08 (0.351)
5.83 ± 1.16
0.16 (0.66)
TG, mmol/L
3.57 ± 1.48
0.13 (0.72)
2.85 ± 1.31
0.12 (0.153)
0.049 \0.001
LDL-C, mmol/L
3.14 ± 0.82
0.37 (\ 0.001)
2.83 ± 0.67
0.59 (\ 0.001)
0.001
HDL-C, mmol/L
2.09 ± 0.63
0.17 (0.403)
2.14 ± 0.38
0.08 (0.352)
0.34
Lp-PLA2, ng/ml
210.67 ± 17.98
–
174.72 ± 30.26
–
\0.001
the protocol described by Emmanouil [13], samples were incubated in microtiter plate wells with immobilized monoclonal antibody (2C10) against Lp-PLA2. The enzyme was identified by a second monoclonal anti-LpPLA2 antibody (4B4) labeled with horseradish peroxidase. The standard used was recombinant Lp-PLA2. The average CV was 5.62 %, with no cross-reactivity with other A2 phospholipases. Analyses of all the samples, standards, and controls were run in duplicate.
5.83 ± 1.16) mmol/L, TG (3.57 ± 1.48 vs. 2.85 ± 1.31) mmol/L, LDL-C (3.14 ± 0.82 vs. 2.83 ± 0.67) mmol/L, and Lp-PLA2 mass (210.67 ± 17.98 vs. 174.72 ± 30.26) ng/ml were significantly higher (P \ 0.05) in PE group than those in the control. There were no significant difference in the average of age (28.4 ± 4.7 vs. 27.4 ± 4.5) year-old, parity (1.41 ± 0.6 vs. 1.46 ± 0.7) times, HDL-C (2.09 ± 0.63 vs. 2.14 ± 0.38) mmol/L (P [ 0.05) (Table 1).
Statistical analysis
Correlation between Lp-PLA2 and A-BMI, BP and Lipid parameters
Statistical analyses were performed using the Statistical Program for Social Sciences (SPSS) software for Windows, version 20.0 (Chicago, IL). Chi square test was used to compare the prevalence of hypertension and normotension in PE and Control group. Differences of parameters were analyzed by using the independent-sample t test or the Mann–Whitney U test as appropriate. Results were presented as mean ± SD. Relationship between Lp-PLA2 and other variables was evaluated by using Spearman’s correlation analysis. Binary logistic regression analysis was used with BP as the dependent variable. P \ 0.05 was considered statistically significant. ROC curve analysis was used to evaluate the predicted value of hypertension risk with Lp-PLA2 in PE patients.
Result
Spearman’s correlation analysis using Lp-PLA2 as the dependent variable and P-BMI, BP(SBP and DBP) and lipid profiles as independent variables showed that serum level of Lp-PLA2 positively correlated with SBP (r = 0.31, P = 0.03) and LDL-C (r = 0.37, P \ 0.01) in PE group. In control group, it is positively correlated with LDL-C (r = 0.59, P \ 0.01) (Table 1). The situation of postpartum follow-up From February to April in 2013, 153 cases in the PE group and 132 in the control group were re-called. The average of follow-up time in PE Group is 2.4 ± 0.3 years (the longest is 3.1 years, while the shortest is 1.5 years). Within the control group, the average is 2.4 ± 0.4 years (the longest is 3.0 years, while the shortest is 1.4 years). No significant difference was showed between the two groups.
Comparison of general information and lipid parameters and Lp-PLA2 mass
The incidence of hypertension
Pro-gestation BMI (22 ± 3.3 vs 20.2 ± 1.8) kg/m2, SBP (154.9 ± 16.1 vs. 112.6 ± 10.4) mmHg, DBP (97.6 ± 11.7 vs. 68.7 ± 7.6) mmHg, TC (6.13 ± 1.38 vs.
The incidence of postpartum hypertension in the PE group was 16.83 %, which was higher than that in the normal control group (1.01 %, P \ 0.001).
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Heart Vessels Fig. 1 Receiver operating characteristic (ROC) curves for pro-gestational BMI, SBP, DBP and laboratory parameters in women with hypertension in PE group
Binary logistic analysis between postpartum hypertension and prenatal factors We supposed the occurrence of postpartum hypertension as dependent variable. TC, TG, HDL-C, LDL-C, and LpPLA2 were regarded as independent variables. The results showed that postpartum hypertension is correlated to LpPLA2(OR 1.134, 95 % CI 1.086–1.185, P \ 0.05), HDL-C (OR 1.698, 95 % CI 0.997–2.891, P = 0.005), and LDL-C (OR 0.43, 95 % CI 0.209–0.886, P = 0.022). After adjusting other factors, it indicated that Lp-PLA2 mass was an independent risk factor for PE postpartum hypertension (OR 1.134,95 % CI 1.086–1.185).
The predicted value of hypertension risk with Lp-PLA2 in PE The area under the ROC curves was 0.882 (95 % CI 0.82–0.92) for postpartum hypertension. The sensitivity of predicting postpartum hypertension was 73.2 % and the specific degree was 86.6 %, with Lp-PLA2 level of 217.75 ng/mL for boundary value. The areas of progestational BMI (0.54, 95 % CI 0.46–0.62), SBP (0.61, 95 % CI 0.53–0.69), DBP (0.57, 95 % CI 0.49–0.65), TC (0.52, 95 % CI 0.43–0.61), TG (0.54, 95 % CI 0.46–0.62), HDL-C (0.58, 95 % CI 0.5–0.66), and LDL-C (0.58, 95 % CI 0.5–0.66) were totally lower than 0.7, which means with little predicting value. (Fig. 1)
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Discussion Relation between Lp-PLA2 and postpartum hypertension Compared with normal pregnant women, women in PE group had significantly higher levels of TC, TG, and LDLC, but lower HDL-C. These results demonstrated that PE exists in abnormal lipid metabolism during pregnancy. Logistic analysis suggested that LDL-C and HDL-C were independent risk factors for postpartum hypertension, indicating prenatal lipid metabolism was indeed linked with postpartum hypertension. To meet the needs of maternal and fetal growth and development in normal pregnancy, lipid metabolism is relatively higher than in progestation stages. However, this condition is much more severe in PE. Clausen et al. [14] found that hypertriglyceridemia appearing before the 20th week of gestation was associated with early onset of PE. Compared with normal pregnant women, TG concentration in PE patients is significantly elevated. Increasing oxidative stress is linked to a direct damage to endothelial cells and stimulates endothelial adhesion molecule (as VCAM-1) and coagulation factor (PAI–1) expression [15, 16]. The inflammatory cells combine, thereby expanding the endothelial inflammation. Elevated TG also has a tendency to accumulate in blood vessels (e.g., uterine spiral artery), impairing endothelial tissues by producing small and dense LDL directly or indirectly. The accumulation of LDL in blood vessel walls can be oxidized to oxLDL [17]. The
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latter activates the receptor LOX-1 to promote adhesion molecule genes (MCP-1, ICAM-1, VCAM-1, P-select element and so on) and ultimately induces inflammatory cells to adhere to blood vessel walls. The endothelial cells take in LOX-1, leading to endothelial dysfunction with the destruction of endothelial integrity or even secretion disorder, thus forming endothelial injury. Hypercholesterolemia participates in endothelial damage in PE by lipid peroxidation [18]. Lipid peroxide and free radicals produced by lipid oxidation damage vascular endothelial tissues directly and prompt platelet adhesion and aggregation. Moreover, irregular blood pressure appears, symptomatic of a series of pathological changes of vasospasm contractions that leads to the occurrence of PE [18]. Similar to the mechanisms mentioned above, dyslipidemia also promotes the development of hypertension by inducing inflammation and oxidative stress. Previous studies suggest that the rise of TG and LDL and the decline of HDL can increase the risk of hypertension [19–22]. Animal studies have proven that chronic low-grade inflammation status in renal tubules is closely related to high blood pressure. For example, in all hypertension animal models, T lymphocytes and macrophages invade the renal tubules–interstitial cells. Renal interstitial inflammation in hypertension is always accompanied by invasion of inflammatory cells and reactive oxygen species (ROS) and angiotensin II produced by kidney cells. Low-grade inflammation of the renal tubules can induce high blood pressure in mice. At the same time, high blood pressure itself can increase chemical factors and adhesion molecules by oxidative stress to promote inflammatory response and further remodeling of vascular structures [23]. Clinical studies have also found that inflammatory mediators increase in patients with high blood pressure. An 11-year follow-up study [24] found that the men whose basic level of c-reactive protein (CRP) were higher than 3.0 mg/L were at higher risk of developing hypertension in the future compared with men whose CRP were lower than 1.0 mg/L. Sesso et al. [25] found that women with higher levels of CRP had higher risk of hypertension compared with those with lower CRP levels. A retrospective study [26] found that increase in plasma fibrinogen, a1-antitrypsin, haptoglobin, ceruloplasmin, and orosomucoid in individuals can lead to elevated blood pressure in the future. Spaan et al. [27] found that the onset of hypertension was linked with obesity, higher fasting insulin, low-density lipoprotein, albuminuria, and delivery time. Further analysis found that an increase in the components of the metabolic patterns (blood pressure, glucose and lipids) will likely increase the risk of hypertension. Thus, glucose and lipid metabolic abnormalities may promote postpartum hypertension. However, in our ROC curve analysis, lipid metabolism was not found to have a prediction of
postpartum hypertension in the future, implying that a different mechanism is involved in lipid metabolism and hypertension. We found a significant increase in the PE group of prenatal Lp-PLA2 with the changes linked to LDL. Furthermore, an increase in Lp-PLA2 expression may increase the risk of postpartum hypertension. Our study suggested that abnormal lipid metabolism during gestation may increase the risk of hypertension in the future by promoting vascular inflammation. Lavi ea al. [28] found that the level of Lp-PLA2 in circulation was associated with coronary endothelial function. Early atherosclerosis was detected in patients through three-dimensional vascular remodeling. The atherosclerosis degree was determined by the amount of LpPLA2, as well as by the increase in the levels of lyso-PC. Lyso-PC is one of the products of Lp-PLA2 from hydrolysis of phospholipids, which is linked to oxidative stress. Lyso-PC formation is one of the mechanisms that induce atherosclerosis. Thus, Lp-PLA2 is an inflammation marker related to oxidative stress, it is also involved in endothelial injuries. We also found that Lp-PLA2 was related to prenatal systolic blood pressure levels. High blood pressure can lead to significant increase in shear force of vascular blood flow (turbulent formation), causing arterial injuries. Adhesion molecules expressed by impaired endothelial cell promote aggregation of white blood cells in the subcutaneous tissue. White blood cells produce interleukin, cytokines, and active oxygen-free radicals, which eventually lead to abnormal inflammatory response in the arterial walls [29, 30]. Overall, PE patients showed a certain degree of vascular inflammation, which is not only related to the severity of the disease but may also be involved in the onset of hypertension in the future. Predictive value of Lp-PLA2 in hypertension In this study, we found that Lp-PLA2 had a negative predictive value in postpartum hypertension of PE. Nguyen et al. [31] found that BMI has a predictive role in hypertension, in which women’s ROC area was 0.62 (95 % CI: 0.58–0.65). After age adjustment, the ROC area was 0.71 (95 % CI: 0.68–0.74). The highest sensitivity and specific degree was 23.5 kg/m2. Kuklinska et al. [32] found that biomarkers of oxidative stress and endothelial injury also have predictive effects for hypertension, with prostaglandins (ROC area of 0.647) as the most profound. Lp-PLA2 is a biomarker that is linked to lipid metabolism and may reflect the state of endothelial damage of vascular inflammation. Thus, Lp-PLA2 detection may lead to a possible higher predictive value in hypertension.
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Prospects The onset of postpartum hypertension in PE patients may contribute to vascular inflammation, which is associated with antepartum lipid metabolism. Furthermore, vascular inflammation has an important function in the formation of atherosclerosis (AS) and cardiovascular disease (CVD). Kajiya et al. [33] reported that serum adipocyte fatty acidblinding protein (A-FABP) might be involved in coronary plaque vulnerability by its critical role in the development of AS by organizing macrophage cholesterol trafficking and inflammation. Similarly, Lp-PLA2 is also one of predictive inflammatory markers of cardiovascular risk. The most important expectation of our study is whether LpPLA2 can use to decrease CVD risk for women with PE history. As PE had been considered as a CVD risk factor for females [34], Lp-PLA2 should be detected not only to predict hypertension, but also to ascertain information relating other CVDs and Lp-PLA2. Lipid-lowering treatment may be an effective action for this expectation. For example, Ezetimibe is a lipid-lowering drug that can efficiently decreases LDL-C and may have an important role in preventing AS by its lipid-lowering and anti-inflammatory effect [35]. It had been reported that Ezetimibe could significantly decrease total plasma Lp-PLA2 mass [36]. All of these are need further studies including long-time follow-up for PE patient and even the adverse effects of lipidlowering drug on pregnant women. Acknowledgment This study was supported by a grant from Guangdong Science and Technology Department, Fund Code: 2011B31800264.
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