CLINICAL RESEARCH: CORONARY ARTERY DISEASE
Relation Between Lipoprotein(a) and Fibrinogen and Serial Intravascular Ultrasound Plaque Progression in Left Main Coronary Arteries
Marc Hartmann, MD*,
Clemens von Birgelen, MD, PhD*,*,
Gary S. Mintz, MD ,
Martin G. Stoel, MD*,
Holger Eggebrecht, MD ,
Heinrich Wieneke, MD,
Martin Fahy, MSc,
Till Neumann, MD,
Job van der Palen, MSc*,
Hans W. Louwerenburg, MD*,
Patrick M.J. Verhorst, MD, PhD* and
Raimund Erbel, MD
* Department of Cardiology, Medisch Spectrum Twente, Enschede, the Netherlands
Department of Cardiology, Essen University, Essen, Germany
Cardiovascular Research Foundation, New York, New York
Manuscript received February 10, 2006;
revised manuscript received March 21, 2006,
accepted March 28, 2006.
* Reprint requests and correspondence: Dr. Clemens von Birgelen, Medisch Spectrum Twente, Thoraxcentrum Twente, Cardiology Department, Haaksbergerstraat 55, 7513ER Enschede, the Netherlands. (Email: von.birgelen{at}12move.nl).
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Abstract
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OBJECTIVES: Patients with elevated lipoprotein(a) [Lp(a)] and fibrinogen levels have an increased risk of coronary heart disease and adverse cardiovascular events. There is evidence that coronary plaque progression is linked to a higher risk for future cardiovascular events.
BACKGROUND: There are no data demonstrating a relation between Lp(a), fibrinogen, and directly measured coronary plaque progression over time.
METHODS: We performed a retrospective analysis of serial intravascular ultrasound (IVUS) studies of 60 left main stems (18 ± 9 months apart) to evaluate plaque progression in relation to Lp(a) and fibrinogen levels and association with adverse cardiovascular events.
RESULTS: There was a positive correlation between Lp(a) (r = 0.58; p < 0.0001), fibrinogen (r = 0.48; p < 0.0001), and changes in plaque-plus-media area. Patients with plaque progression (n = 41) had higher Lp(a) (30 ± 26 mg/dl vs. 14 ± 9 mg/dl; p < 0.0012) and fibrinogen (295 ± 88 mg/dl vs. 240 ± 72 mg/dl; p = 0.019) levels than patients with plaque regression (n = 19). Multivariate linear regression analysis showed Log Lp(a) (regression coefficient = 9.45; p = 0.0008) but not fibrinogen to be independently associated with plaque progression. A total of 19 patients suffered from adverse cardiovascular events; they had higher Lp(a) (44 ± 30 mg/dl vs. 16 ± 12 mg/dl; p < 0.0001) and fibrinogen (342 ± 73 mg/dl vs. 248 ± 76 mg/dl; p < 0.0001) levels. Multivariate logistic regression analysis showed Log Lp(a) (odds ratio 10.20, 95% confidence interval 2.36 to 44.13; p = 0.0019) and fibrinogen (odds ratio 1.01, 95% confidence interval 1.00 to 1.03; p = 0.018) were independently associated with adverse cardiovascular events.
CONCLUSIONS: Serial IVUS showed a positive correlation between Lp(a) and fibrinogen levels and plaque progression. Lp(a), but not fibrinogen, remains independently associated with plaque progression. In addition, the present data suggest a considerable incremental value of Lp(a) in predicting cardiovascular risk.
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Abbreviations and Acronyms
| | CI = confidence interval | | CSA = cross-sectional area | | EEM = external elastic membrane | | HDL = high-density lipoprotein | | IVUS = intravascular ultrasound | | LDL = low-density lipoprotein | | Lp(a) = lipoprotein(a) | | PCI = percutaneous coronary intervention | | P&M = plaque plus media |
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Lipoprotein(a) [Lp(a)] and fibrinogen have been shown to serve as predictors of coronary heart disease and fatal cardiovascular events (1–10). Patients with elevated Lp(a) and fibrinogen levels have an increased risk of coronary heart disease (11,12) and cardiovascular events (12–14). There is evidence that plaque progression in coronary arteries is linked to a higher risk of future fatal or nonfatal cardiovascular events (15,16). Lipoprotein(a) is associated with plaque progression, as indirectly assessed by lumen changes in short-term (17,18) and long-term (19,20) angiographic follow-up, and with calcium score changes as measured by sequential electron beam computerized tomography (21). There are no data demonstrating directly the relation between Lp(a), fibrinogen, and coronary plaque progression.
Intravascular ultrasound (IVUS) imaging permits measurements of total vessel, lumen, and plaque dimensions in vivo (22). Serial IVUS is an ideal tool to directly assess progression or regression of atherosclerotic plaques in native coronary arteries in relation to serum parameters (23–25). In the present observational study we retrospectively analyzed serial IVUS ( 12 months) data of nonstenotic left main coronary arteries to test whether Lp(a) and fibrinogen levels predict the progression of coronary atherosclerosis and the onset of adverse cardiovascular events (beyond the information provided by classic risk factors) and whether potential relations are independent of each other.
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Methods
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Study population.
We performed a retrospective analysis of Lp(a) and fibrinogen levels in relation to serial IVUS studies of atherosclerotic left main coronary plaques in a population that has been reported previously (25). All plaques were de novo, hemodynamically nonsignificant, and met the following criteria: 1) serial high-quality IVUS of the entire left main artery 12 months apart; 2) calcifications that did not limit quantitative assessment of vessel cross-sectional area (CSA); 3) nonostial plaque location; 4) angiographic lumen diameter stenosis <30% ("worst view" visual assessment); and 5) no intervention in the very proximal left anterior descending or circumflex coronary arteries, because these interventions could have affected the left main artery. Patients were examined in the Essen University Cardiac Catheterization Laboratory (a tertial referral center) with a follow-up of 18 ± 9 months (median 14 months, range 12 to 50 months). As previously reported, this represents consecutive patients who underwent initial IVUS examination during coronary intervention and then returned after a 1- to 2-year period for repeat IVUS examination (25). No patient had a myocardial infarction within 3 months before the index examination. At Essen University, patients with previous IVUS who returned for recatheterization were routinely examined with IVUS as part of the clinical protocol. In none of these patients was IVUS performed as part of another study. This IVUS study was approved by the Local Council on Human Research, and all patients signed a written informed consent form as approved by the local medical ethics committee.
Cardiovascular risk factors, parameters, and medication.
In our laboratory we record demographics, cardiovascular risk factors, medications, and results of key laboratory tests of patients examined with IVUS. All baseline blood samples were collected from the same site (periphereal vein) 27 ± 8 h before percutaneous catheterization (26) and analyzed in the central laboratory of Essen University according to international standards. Plasma concentrations of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides were measured by standard enzymatic methods. Total cholesterol/HDL-C and LDL-C/HDL-C ratios were calculated. Lipoprotein(a) levels were quantitated by nephelometry after addition of an antiserum (Behringwerke, Marburg, Germany) (27). Fibrinogen was measured by determining the coagulation time of prediluted citrated plasma in the presence of a large amount of thrombin (Behringwerke). Baseline data of all laboratory variables were used for statistical analyses. Cardiovascular risk factors that were recorded included diabetes mellitus and hypertension (both medication-dependent only), history of smoking, and family history of coronary artery disease. Medications were recorded only if drugs were taken for >50% of the follow-up interval (e.g., clopidogrel for 4 weeks was not tabulated).
IVUS imaging.
The IVUS imaging was performed as previously described (25). In brief, IVUS studies were performed during percutaneous coronary interventions (PCI) of middle or distal left anterior or circumflex arteries after intracoronary injections of 200 µg nitroglycerin with commercially available IVUS systems: a mechanical sector scanner (Boston Scientific, San Jose, California) incorporating a 30-MHz single-element beveled transducer or a solid-state device (Endosonics, Rancho Cordova, California). Importantly, at Essen University, if a patient undergoes imaging with one IVUS system during an index procedure, the same IVUS system is used at follow-up. Slow continuous pullbacks were generally performed using a motorized pullback device (at 0.5 mm/s). In addition, a dedicated image-in-image system (Echo-Map; Siemens, Erlangen, Germany) was used to record the "angiographic" position of the IVUS probe together with the corresponding IVUS image (28).
Quantitative IVUS analysis.
The left main target site image slice was determined from the initial IVUS study as previously described (25); this was the site with the smallest lumen CSA within the plaque. Exact matching of the target site on initial and follow-up IVUS studies was ensured using side-by-side comparison of end-diastolic IVUS images of the two IVUS sequences along with the pullback speed, the operators’ recorded comments (on videotape), and characteristic calcifications, vascular and perivascular landmarks, and plaque shapes. If required, X-ray sequences of the dedicated image-in-image system (Echo-Map) were revisited to optimize matching (28).
The lumen CSA was measured by tracing the leading edge of the intima. The external elastic membrane (EEM) CSA was measured by tracing the leading edge of the adventitia. Plaque plus media (P&M) CSA was calculated (as EEM – lumen CSA). Extrapolation of the EEM boundary behind calcium was possible if each individual calcific deposit did not shadow >75° of the adventitial circumference. To compensate for variations in follow-up intervals and to obtain comparable data, we calculated absolute and relative changes ( ) between initial and follow-up IVUS data; measurements were normalized for the length of the follow-up period (changes per year) and baseline variables.
Statistical analysis.
Analyses were performed with SPSS 10.0.7 (SPSS Inc., Chicago, Illinois). Dichotomous data are presented as frequencies. Quantitative data are presented as mean ± 1 SD and were compared using Student t test, Mann-Whitney U test, and regression analysis. Correlation analyses were performed with nonparametric Spearman test (r = Spearman correlation coefficient). Because the distribution of Lp(a) was skewed it was log transformed (Log) to obtain a normal distribution and more reliable estimates for multivariate regression analyses. A p value of <0.05 was considered significant.
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Results
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Demographics, medication, and laboratory testing of patients.
Demographics, medication, and baseline laboratory testing of the study population (n = 60) are presented in Table 1. We found a positive correlation (r = 0.49; 95% confidence interval [CI] 0.27 to 0.66; p = 0.0001) between Lp(a) (median 14.5 mg/dl, range 6.2 to 125.0 mg/dl) and fibrinogen levels (median 271.0 mg/dl, range 110.0 to 510.5 mg/dl).
Relation between Lp(a) and serial IVUS data.
There was a positive correlation between annual changes in P&M CSA versus Lp(a) levels (r = 0.58; 95% CI 0.39 to 0.73; p < 0.0001) (Fig. 1). There was a negative correlation between annual changes in lumen CSA versus Lp(a) levels (r = –0.24; 95% CI –0.55 to –0.10; p = 0.007) (data not shown) and no correlation between annual changes in EEM CSA versus Lp(a) levels (r = 0.01; 95% CI –0.25 to 0.26; p = 0.95) (data not shown). Patients with P&M CSA increase (n = 41) had significantly higher Lp(a) levels than patients with P&M CSA decrease (n = 19) (30 ± 26 mg/dl vs. 14 ± 9 mg/dl; p < 0.0012).
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Figure 1 Lipoprotein(a) and fibrinogen serum levels versus annual changes in plaque plus media (P&M) cross-sectional area (CSA). r = Spearman correlation coefficient. Dotted regression lines were derived from linear regression analysis.
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Relation between fibrinogen and serial IVUS data.
There was a positive correlation between annual changes in P&M CSA versus fibrinogen levels (r = 0.48; 95% CI 0.25 to 0.65; p < 0.0001) (Fig. 1). There was no significant correlation between annual changes in lumen CSA versus fibrinogen levels (r = –0.23; 95% CI –0.46 to 0.02; p = 0.07) (data not shown) and no correlation between annual changes in EEM CSA versus fibrinogen levels (r = 0.11; 95% CI –0.15 to 0.35; p = 0.42) (data not shown). Patients with P&M CSA increase (n = 41) had significantly higher fibrinogen levels than patients with P&M CSA decrease (n = 19) (295 ± 88 mg/dl vs. 240 ± 72 mg/dl; p = 0.019).
Multivariate analysis of predictors of P&M CSA increase.
Multivariate linear regression analysis was used to determine predictors of the increase in P&M CSA (Table 2). The following were tested in the multivariate model: Log Lp(a), fibrinogen, LDL-C, HDL-C, total cholesterol, total cholesterol/HDL-C ratio, LDL-C/HDL-C ratio, smoking, hypertension, diabetes, family history, age, and use of statins (LDL-C, HDL-C, and smoking were shown in a previous publication to be univariate predictors of the increase in P&M CSA in these patients [16]). Independent predictors were Log Lp(a) (p = 0.0008) and smoking (p = 0.0001); LDL-C (p = 0.078) showed a trend, whereas fibrinogen was not an independent predictor (Table 2).
Lp(a) and fibrinogen and adverse cardiovascular events.
During follow-up, 6 patients (10%) suffered from acute myocardial infarction, 7 (12%) from unstable angina, and 6 (10%) from PCI of a new de novo coronary lesion. The mean interval between baseline laboratory test and adverse event during follow-up was 450 ± 98 days. Patients with adverse cardiovascular events (n = 19) had higher Lp(a) (44 ± 30 mg/dl vs. 16 ± 12 mg/dl; p < 0.0001) and fibrinogen levels (342 ± 73 mg/dl vs. 248 ± 76 mg/dl; p < 0.0001) than patients without adverse events (n = 41) (Fig. 2, Table 3). In addition, patients with adverse events had significantly higher total cholesterol/HDL-C and LDL-C/HDL-C ratios and significantly more annual increase in P&M CSA than patients without events (Table 3).
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Figure 2 Lipoprotein(a) and fibrinogen serum levels in patients with and without adverse cardiovascular events. AMI = acute myocardial infarction; PCI = percutaneous coronary intervention; UAP = unstable angina pectoris.
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Table 3. Laboratory Tests and Serial IVUS Data of Patients With and Without Clinical End Points and/or Revascularization Procedures During Follow-Up
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Multivariate analysis of predictors of adverse cardiovascular events.
Multivariate logistic regression analysis was used to determine predictors of adverse cardiovascular events during follow-up (Table 4). The following were tested in the multivariate model: Log Lp(a), fibrinogen, LDL-C, HDL-C, total cholesterol, total cholesterol/HDL-C ratio, LDL-C/HDL-C ratio, smoking, hypertension, diabetes, familiy history, age, use of statins, and increase in P&M CSA. Independent predictors were Log Lp(a) (p = 0.0019) and fibrinogen (p = 0.018) (Table 4).
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Table 4. Multivariate Predictors of Adverse Cardiovascular Events (Clinical End Points and/or Revascularization Procedures) During Follow-Up
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Discussion
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Lp(a) and coronary plaque progression.
Previous studies revealed Lp(a) as a predictor of coronary heart disease (3,7), angiographic severity, and extent of the disease process (3). However, other studies failed to demonstrate an association between Lp(a) and cardiovascular disease (29,30). In good agreement with our findings, Lp(a) levels showed a strong correlation with serial plaque progression assessed in previous angiographic (17–20) and electron beam tomographic studies (21). Uchida et al. (18) showed Lp(a) to be an independent predictor of angiographic lesion progression at 6 months follow-up, and Matsumoto et al. (19) showed that the Lp(a) level was significantly associated with angiographic disease progression after more than 24 months. In support of this, we found a positive correlation between Lp(a) levels versus annual changes in P&M CSA. In addition to smoking, Lp(a) was an independent predictor of plaque progression in a multivariate analysis (LDL-C showed only a trend). The cluster of Lp(a) levels around 10 mg/dl does not permit defining an exact threshold below which no plaque progression occurs. However, the mean Lp(a) level of patients with plaque progression was 30 mg/dl, whereas it was 14 mg/dl in patients without plaque progression (p = 0.0012). Such Lp(a) values (around 30 mg/dl) were also found in previous serial angiographic studies to be associated with long-term plaque progression (19).
The pathophysiologic role of Lp(a) in atherosclerotic disease progression is explained by the accumulation of Lp(a) in the vessel wall and its ability to promote cholesterol accumulation in macrophages forming foam cells and subsequent fatty streaks (31,32) and to promote smooth muscle cell proliferation and migration in atherosclerotic lesions by inactivating transforming growth factor-beta (33). Lipoprotein(a) is considered to have an inhibitory effect on fibrinolytic mechanisms owing to its structural similarity to plasminogen causing competition with plasminogen activators; intraluminal thrombus formation may also cause reparative proliferative response of the vascular wall (17,31,32).
Fibrinogen and coronary plaque progression.
It has been demonstrated that fibrinogen may also be associated with severity and extent of coronary atherosclerosis (8,9) and with electron beam tomography-assessed calcium score (10). In support of this, we found a positive correlation between fibrinogen levels versus annual changes in P&M CSA. However, fibrinogen was not an independent predictor of plaque progression in a multivariate analysis. Fibrinogen affects blood rheology and platelet aggregation, which play a role in atherogenesis (34). Nevertheless, the mechanisms by which fibrinogen may promote atherosclerosis progression remains to be determined (6).
Vascular remodeling.
In the present study we found no relation between Lp(a) or fibrinogen levels versus actual arterial remodeling (EEM CSA). One nonserial IVUS study found no relation between Lp(a) levels and the remodeling index, defined as the ratio of the lesion EEM CSA to the reference EEM CSA (35). In addition, other blood chemistries that are associated with atherogenesis (total cholesterol, LDL-C, HDL-C, triglycerides, and C-reactive protein) also had no impact on arterial remodeling (35).
Relation between Lp(a), fibrinogen, and adverse cardiovascular events.
A correlation between Lp(a) and fibrinogen concentrations has been reported (36) but was not consistently found in the majority of previous studies (37). In the present study population, Lp(a) levels correlated directly with fibrinogen levels. In vitro studies showed that over time Lp(a) binds with fibrinogen in a concentration-dependent manner (38). The deposition of Lp(a) within the fibrin clot is believed to be a contributing factor in atherogenesis, promoting plaque progression (31,32,38). Study patients with plaque progression had significantly higher Lp(a) and fibrinogen levels. However, only Lp(a) was an independent predictor of plaque progression.
On the other hand, the association between Lp(a) and fibrinogen levels may indicate a multiple unstable plaque phenotype (advanced disease); fibrinogen may be elevated as part of the acute phase response, and Lp(a) has also been shown to rise after plaque destabilization (26). Two clinical studies showed that patients with elevated serum Lp(a) levels, when associated with high fibrinogen levels, had a significantly increased cardiovascular disease risk (11,12). Peak serum levels of Lp(a) and fibrinogen seem to coincide with the morning peak frequencies of myocardial infarction and stroke (14). Accordingly, we found that patients with adverse cardiovascular events had significantly higher serum levels of both Lp(a) and fibrinogen than patients who were event free during follow-up. In a multivariate model, Lp(a) and fibrinogen were independent predictors of adverse cardiovascular events. Our data suggest in particular an incremental value of Lp(a) in predicting cardiovascular risk (beyond the information provided by classic risk factors).
Study limitations.
By most standards, this was a large serial IVUS study; however, all current studies with long-term serial IVUS assessment of atherosclerosis are limited to a relatively small number of patients. This was a retrospective analysis, and we included only patients with established coronary artery disease and repeat cardiac catheterization 12 months after baseline. About a third of the subjects experienced a clinical event during a follow-up of only 18 months in spite of adequate therapy and prevention. Accordingly, this is a very high-risk group. Because of this selection bias, the findings of the current study may not be applicable to a standard population with coronary artery disease or even the general population without established disease. Other superior markers of inflammation (e.g., high-sensitivity C-reactive protein) were not available for the present study population. We used 2 IVUS systems in the present study; although this approach may have minor shortcomings, every effort was taken to obtain the most reliable data possible, as previously discussed in detail (25). Three-dimensional analyses may be superior for the assessment of coronary dimensions and provide volumetric data (39). We studied only left main artery disease as representative of nonintervened coronary segments.
Conclusions.
We found a positive correlation between Lp(a) and fibrinogen levels versus annual changes in P&M CSA. Lipoprotein(a) was an independent predictor of plaque progression (regression coefficient = 9.45), with a mean Lp(a) level of 30 mg/dl in patients with plaque progression. Lipoprotein(a) and fibrinogen were independent predictors of adverse cardiovascular events during follow-up in this group of patients. The data suggest in particular a considerable incremental value of Lp(a) in predicting cardiovascular risk.
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Abstract
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