| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
|
Interact CardioVasc Thorac Surg 2009;9:467-470. doi:10.1510/icvts.2009.208843 © 2009 European Association of Cardio-Thoracic Surgery
Circulating lipoprotein(a) concentrations and abdominal aortic aneurysm presenceDepartment of Cardiovascular Surgery, Shizuoka Medical Center, 762-1 Nagasawa, Shimizu-cho, Sunto-gun, Shizuoka 411-8611, Japan Received 2 April 2009; received in revised form 7 June 2009; accepted 10 June 2009
*Corresponding author. Tel.: +81 559752000; fax: +81 559752725.
To summarize the present evidence for an association between circulating lipoprotein(a) [Lp(a)] and abdominal aortic aneurysm (AAA) presence. MEDLINE database was searched to identify all case–control studies that compared circulating Lp(a) concentrations between patients with AAA and subjects without AAA. For each study, data regarding Lp(a) concentrations in both the AAA and control groups were used to generate standardized mean differences (SMDs) and 95% confidence intervals (CIs). Study-specific estimates were combined using inverse variance-weighted average of logarithmic SMDs in both fixed- and random-effects models. Our search identified five case–control studies. In total, our meta-analysis included data on 982 cases with AAA and 1296 controls without AAA. Pooled analysis of the five studies demonstrated significantly higher Lp(a) concentrations in the AAA group than those in the control group in random-effect models (SMD, 0.26; 95% CI, 0.08–0.44; P=0.005). There was significant study heterogeneity of results (P=0.03) but no evidence of significant publication bias (P=0.3272). We found that circulating Lp(a) concentrations are likely higher in cases with AAA than in controls without AAA. Higher circulating Lp(a) concentrations may be associated with AAA presence.
Key Words: Lipoprotein(a); Abdominal aortic aneurysm; Biological markers
Increased circulating lipoprotein(a) [Lp(a)] concentrations are predictive for several forms of vascular disease, including coronary artery disease [1], peripheral arterial disease [2], and ischemic stroke [3]. Several investigators have measured and compared circulating Lp(a) in patients with abdominal aortic aneurysm (AAA) and subjects without AAA to assess its possible role in the pathogenesis or progression of AAA. Circulating Lp(a) concentrations could play a role in the diagnosis of AAA and may have a role in predicting subsequent progression of AAA. To summarize the present evidence for an association between circulating Lp(a) and AAA presence, we performed a systematic review and meta-analysis of case–control studies that compared circulating Lp(a) concentrations between patients with AAA and subjects without AAA.
2.1. Search strategy All case–control studies that compared circulating Lp(a) concentrations between patients with AAA and subjects without AAA were identified using a two-level search strategy. First, a public domain database (MEDLINE) was searched using a Web-based search engine (PubMed). Second, relevant studies were identified through a manual search of secondary sources including references of initially identified articles and a search of reviews and commentaries. All references were downloaded for consolidation, elimination of duplicates, and further analysis. The MEDLINE database was searched from January 1966 to December 2008. MeSH keywords included lipoprotein(a); and aortic aneurysm, abdomen. Text keywords included lipoprotein(a) [Lp(a)], and abdominal aortic aneurysm. 2.2. Study selection and data abstraction Studies considered for inclusion met the following criteria: the design was a case–control study; the study population was patients with AAA and subjects without AAA; and main outcomes included means and standard deviations (S.D.s) of circulating Lp(a) concentrations in the AAA and control groups. Data regarding detailed inclusion criteria and Lp(a) concentrations were abstracted (as available) from each individual study. We conducted a meta-analysis of summary statistics from the individual studies because detailed, patient-level data were not available for all studies. For each study, data regarding circulating Lp(a) concentrations in both the AAA and control groups were used to generate standardized mean differences (SMDs) and 95% confidence intervals (CIs), because plasma or serum Lp(a) concentrations were stated. To convert mg/dl to nmol/l, the values (mg/dl) were multiplied by 35.7. In articles reporting the median and interquartile range (IQR), we took the median to be representative of the mean and converted the IQR into a S.D. by dividing it by 1.35. When a P-value that related to the difference between means in two groups was stated, a S.D. was obtained from the P-value by the use of standard formulae in the Cochrane Handbook for Systematic Reviews of Interventions Version 5.0.1 [updated September 2008] (The Cochrane Collaboration, 2008. Available from www.cochrane-handbook.org). Study-specific estimates were combined using inverse variance-weighted average of logarithmic SMDs in both fixed- and random-effects models. Between study heterogeneity was analyzed by means of standard 2-tests. Where significant statistical heterogeneity was identified, the random-effect estimate was used preferentially as the summary measure. Sensitivity analyses were performed to assess the contribution of each study to the pooled estimate by excluding individual studies one at a time and recalculating the pooled SMD estimates for the remaining studies. Publication bias was assessed graphically using a funnel plot and mathematically using an adjusted rank-correlation test, according to the method of Begg and Mazumdar [4]. All analyses were conducted using Review Manager (RevMan) [5] and Microsoft Excel (Version 11.5.0).
3.1. Search results Our search identified five case–control studies [6–10] that compared circulating Lp(a) concentrations between patients with AAA and subjects without AAA. We excluded the study by Papagrigorakis et al. [11], because only two patients with AAA were included in the 38 cases and only medians (without S.D.s, standard errors (S.E.s), IQRs, and P-values) of Lp(a) concentrations were reported. In total, our meta-analysis included data on 982 cases with AAA and 1296 controls without AAA. Jones et al. [6] measured plasma Lp(a) in patients in whom vascular disease consisted of coronary artery disease, ischemic peripheral vascular disease, ischemic stroke, and AAA; and 230 disease-free controls. We abstracted the data on 425 AAA patients (mean age, 71.7±7.6 years; men, 77.7%) who had infrarenal aneurysms >5 cm in anteroposterior diameter, as determined by ultrasound scan. Controls (mean age, 70.3±6.9 years; men, 33.8%) were recruited from Local Community Groups, with inclusion criteria of age >55 years, no history of ischemic heart disease (including angina pectoris), peripheral vascular disease, stroke (including transient ischemic attack), or AAA and being currently in good general health. The authors determined Lp(a) concentrations by a double-sandwich ELISA using monoclonal antibody (MAb) a-6 as the capture antibody and MAb a-1 as the detection antibody. Sofi et al. [7] evaluated a pattern of serum Lp(a) in 438 patients (median age, 74 [range, 40–94] years; 397 men and 41 women) with AAA (mean diameter, 6.1±1.3 cm) and 438 healthy subjects selected to be comparable for age (median age, 73.4 [range, 48–84] years) and gender (391 men and 47 women) with patients and without instrumental evidence of AAA (mean abdominal aortic diameter, 1.7±1.1 cm). All subjects, patients and controls, underwent duplex scanning examination, and AAA was defined as a focal dilatation of the abdominal aorta at least 1.5 times larger than expected normal diameter. A detailed interview to the controls addressing personal and family history was performed within a physical examination by expert physicians, in order to identify subjects with no symptoms of vascular diseases and to exclude who was suspected of having any kind of vascular disease. Lp(a) was assayed by an ELISA method (Mercodia Apo(a), Mercodia AB, Uppsala, Sweden). Schillinger et al. [8] compared serum Lp(a) between age- and gender-matched pairs samples of patients with AAA, thoracic aortic aneurysm with dissection, and healthy control subjects. We abstracted the data on 41 patients with AAA and 41 healthy control subjects. Healthy individuals without aortic aneurysm, atherothrombotic risk factor (diabetes mellitus, smoking, hypertension, and hyperlipidemia), and medical history and clinical signs of atherosclerotic disease were recruited at the outpatient ward of the emergency department. An aneurysm was defined as a permanent dilatation of the aorta, with diameter of at least 50% greater than the proximal neck, and the diagnosis was established with color-coded duplex sonography and computed tomography scan. Serum Lp(a) was measured with nephelometry on a Behring Nephelometer Analyzer II with the N Latex Lp(a) reagent (Dade Behring, Marburg, Germany), according to the manufacturer's instructions. Franks et al. [9] compared plasma Lp(a) concentration in smokers (in the previous four weeks [current smokers]) with and without clinical AAA. The patients with AAA (cases) comprised 37 men and 7 women (median age, 69.8 years; IQR, 64.9–75.4 years), and the anteroposterior diameter of the aneurysm varied from 5.4 to 9.8 cm. From potential controls recruited from outpatient clinics (orthopedic, dermatology, and urology) and inpatient wards (short stay, urology, general surgery, and orthopedic), up to five or six sex- and ethnic-matched controls (202 men and 42 women; median age, 70.5 years; IQR, 64.8–75.4 years) were selected for each case. Lp(a) was measured by radioimmunoassay (Pharmacia UK) according to the manufacturer's instructions. As part of an ultrasound screening program in a population (men and women) of 65-to 75-year-old (mean, 69±3 years), Simoni et al. [10] measured the Lp(a) plasma level in 343 subjects without an AAA (aortic diameter, <26 mm) and 34 with an aneurysm (diameter, >29 mm). Lp(a) was measured by means of immunoturbidimetric analysis (Incstar reagents, COBAS-MIRA S-Roche analyzer), which had already been shown to be equivalent to the ELISA technique. Difference in measurement techniques (immunoassay kit) might explain the large range in observed values. Three [6–8] of the five individual studies demonstrated significantly higher circulating Lp(a) concentrations, and two studies [9, 10] showed non-significantly higher ones in the AAA group than those in the control group. Pooled analysis of the five studies demonstrated significantly higher Lp(a) concentrations in the AAA group than those in the control group in random-effect models (SMD, 0.26; 95% CI, 0.08–0.44; P=0.005 [Fig. 1]). There was significant study heterogeneity of results (P=0.03) and no difference in the pooled result from fixed-effects modeling (SMD, 0.25; 95% CI, 0.16–0.35; P<0.00001). To assess the impact of qualitative heterogeneity in study design and case selection on the pooled effect estimate, we performed several sensitivity analyses. In general, exclusion of any single study from the analysis did not substantively alter the overall result of our analysis.
3.4. Publication bias To assess publication bias we generated a funnel plot of the effect size vs. the S.E. for each study (Fig. 2). There was no evidence of significant publication bias (P=0.3272 by Begg adjusted rank-correlation test).
3.5. Excluded study Papagrigorakis et al. [11], whose study was excluded from the present meta-analysis, stated in their article that the median plasma Lp(a) protein levels were 8.7 mg/dl for the 32 patients undergoing surgery for aortic aneurysm (note including only two AAAs) and 3.3 mg/dl in 274 control subjects. S.D.s, S.E.s, IQRs, and P-values were not reported.
The results of our analysis suggest that circulating Lp(a) concentrations may be higher in patients with AAA than those in subjects without AAA. Circulating Lp(a) concentrations could play a role in the diagnosis of AAA. Our analysis, however, must be viewed in the context of its limitations. First, there was qualitative heterogeneity in case selection (i.e. definition of AAA) among the included studies. The diameters of AAA were >5 cm [6], 6.1±1.3 cm [7], at least 50% greater than the proximal neck [8], from 5.4 to 9.8 cm [9], >29 mm [10]. Second, we combined not adjusted but crude values of Lp(a) concentrations in the present meta-analysis. Jones et al. [6] determined the adjusted odds ratios (ORs) for increased Lp(a) concentrations as an indicator of AAA risk using multivariate logistic regression. They obtained adjusted ORs of 2.12 (95% CI, 1.37–3.29; P<0.001) using the >45 nmol/l cut-off and 2.54 (95% CI, 1.41–4.56; P=0.002) using the 4th (>45 nmol/l) vs. 1st (<4.5 nmol/l) control quartiles. Whereas, having an Lp(a) <2 nmol/l had no significant effect on the risk of AAA (OR, 0.68; 95% CI, 0.37–1.24; P=0.21). A logistic regression analysis by Sofi et al. [7] showed a significant association between high level of Lp(a) (>300 mg/l) and AAA (OR, 3.3; 95% CI, 2.4–4.6; P<0.0001) at the univariate analysis; and (OR, 2.4; 95% CI, 1.6–3.5; P<0.001) after adjustment for age, gender, and traditional risk factors. Multivariate analysis by Schillinger et al. [8] confirmed an independent association between Lp(a) and AAA: patients with higher Lp(a) serum levels had a significantly increased risk for having an AAA (OR, 1.1; 95% CI, 1.0–1.1; P=0.009). These adjusted findings may strengthen the crude results of our study. Despite these acknowledged limitations, we found that, based on a systematic review and meta-analysis, Lp(a) concentrations are likely higher in cases with AAA than controls without AAA. Higher circulating Lp(a) concentrations may be associated with AAA presence. It is postulated that circulating Lp(a) concentrations measured at diagnosis or during follow-up might provide important prognostic information about subsequent aortic behavior. Two studies, however, have denied the hypothesis. Watt et al. [12] measured Lp(a) in stored serum sample from 30 men who subsequently (average follow-up time, 13 years) died of ruptured AAA and 150 matched controls. There was no significant difference in Lp(a) between the two groups (geometric mean with S.D., 4.16±4.20 mg/dl vs. 3.18±4.09 mg/dl; P>0.1). On multivariate analysis, the association between Lp(a) and ruptured AAA was no longer statistically significant. Lindholt et al. [13] followed 117 male patients with AAA annually with ultrasound investigation for a mean of 2.5 (range, 1–5) years, and Lp(a) did not correlate to expansion: non-parametric correlation coefficients of log[Lp(a)] (mmol/l) focusing on aneurysmal expansion rate (mm/year), 0.11; P=0.33; after multiple linear regression analysis adjusting for smoking. Circulating Lp(a) concentrations may not have a role in predicting subsequent progression of AAA. The type of medications and biometric characteristics might influence the Lp(a) concentrations. However, patients with an AAA were not significantly larger in stature or of greater body weight than those with a normal aorta in the study by Simoni et al. [10], and body mass index was 22.8 (IQR, 21.2–25.4) kg/m2 in the cases with AAA vs. 23.8 (IQR, 21.7–26.5) kg/m2 in the controls (P=0.272) in the study by Franks et al. [9]. Meanwhile, in the study by Jones et al. [6], 22.4% of the controls vs. 37.0% of the patients with AAA underwent lipid-lowering treatment (P<0.002). Furthermore, the authors [6] specifically examined the independence of the Lp(a) and vascular disease association, from exposure to lipid-lowering therapy (statin or fibrate medications). Although Lp(a) ORs (>45 nmol/l) were slightly reduced when modeled with lipid-lowering therapy, the association of Lp(a), and vascular disease remained significant, both in the combined vascular disease group (coronary artery disease, ischemic peripheral vascular disease, ischemic stroke, and AAA) (OR, 1.76; 95% CI, 1.3–2.4; P<0.0005) and the specific disease subgroups. Within sub-groups, patients on lipid-lowering therapy did not have significantly different Lp(a) concentrations compared with untreated individuals. Significantly, given the now widespread use of lipid-lowering agents (predominantly statin), Lp(a) may be a predictive lipid marker of AAA risk, regardless of exposure to standard lipid-lowering therapy [6]. Besides the presence of AAA, a high level of Lp(a) is predictive of shorter life expectancy. Danesh et al. [14] reported a meta-analysis of the 27 prospective studies with at least one year of follow-up. Comparison of individuals in the top third of baseline plasma Lp(a) measurements with those in the bottom third in each study yielded a combined risk ratio (RR) for coronary heart disease of 1.6 (95% CI, 1.4–1.8), with similar findings when the analyses were restricted to the 18 studies of general populations (combined RR, 1.7; 95% CI, 1.4–1.9). Smolders et al. [15] systematically reviewed the literature to determine whether Lp(a) is a risk factor for stroke. In case–control studies (n=23 with 2600 strokes) unadjusted mean Lp(a) was higher in stroke patients (SMD, 0.39; 95% CI, 0.23–0.54) and was more frequently abnormally elevated (OR, 2.39; 95% CI, 1.57–3.63). In prospective cohort studies (n=5 with >1645 strokes), incident stroke was more frequent in patients in the highest tertile of Lp(a) distribution compared with the lowest tertile of Lp(a) (RR, 1.22; 95% CI, 1.04–1.43). Sofi et al. [16] systematically examined the published data on the association between high Lp(a) levels and venous thromboembolism. The summary ORs of included case–control studies under a fixed-effects model showed a statistically significant association between Lp(a) levels >300 mg/l and venous thromboembolism: 1.87, 95% CI, 1.51–2.30; P<0.0001. Elevated levels of Lp(a) cause endothelial and intimal damage and thus may increase the susceptibility for intimal injury and initiation of aneurysm formation [8]. Detailed role of Lp(a) in the pathogenesis of AAA, however, has been unknown. Further investigation is needed to elucidate the mechanism how Lp(a) affects initiation of aneurysm formation, promotion of aneurysm development, or trigger of aneurysm rupture.
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| ANN THORAC SURG | ASIAN CARDIOVASC THORAC ANN | EUR J CARDIOTHORAC SURG |
| J THORAC CARDIOVASC SURG | ICVTS | ALL CTSNet JOURNALS |
Top
Abstract
1. Introduction
