CLINICAL RESEARCH: METABOLIC SYNDROME, DYSLIPIDEMIA, AND VASCULAR ABNORMALITIES
High lipoprotein(a) levels and small apolipoprotein(a) sizes are associated with endothelial dysfunction in a multiethnic cohort
Henry D. Wu, MD*,*,
Lars Berglund, MD PhD*,
Clarito Dimayuga, MD*,
Jeffery Jones, MS*,
Robert R. Sciacca, EngScD, MS*,
Marco R. Di Tullio, MD* and
Shunichi Homma, MD*
* Department of Medicine, Columbia University, New York, New York, USA
Manuscript received March 3, 2003;
revised manuscript received August 8, 2003,
accepted August 18, 2003.
* Reprint requests and correspondence: Dr. Henry D. Wu, Division of Cardiology, Columbia University, 630 West 168th Street (PH342), New York, New York 10032, USA.
hdw1{at}columbia.edu
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Abstract
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OBJECTIVES: This study sought to determine the effect of lipoprotein(a), or Lp(a), levels and apolipoprotein(a), or apo(a), sizes on endothelial function and to explore ethnic differences in their effects.
BACKGROUND: Although high levels of Lp(a) have been shown to confer increased cardiovascular risk in Caucasians, its significance in non-Caucasian populations is uncertain. The pathogenic role of the apo(a) component of Lp(a) is also unclear.
METHODS: The relationship of Lp(a) levels and apo(a) sizes to endothelial function was examined in a multiethnic cohort of 89 healthy subjects (age 42 ± 9 years; 50 men, 39 women) free of other cardiac risk factors. Endothelium-dependent, flow-mediated dilation (FMD) and endothelium-independent, nitrate-induced dilation (NTG) were assessed by ultrasound imaging of the brachial artery.
RESULTS: Plasma Lp(a) levels were lowest in Caucasians (18.3 ± 21.1 mg/dl, n = 40); intermediate in Hispanics (30.2 ± 30.5 mg/dl, n = 21); and highest in African Americans (68.8 ± 46.0 mg/dl, n = 28). Lipoprotein(a) levels were found to correlate inversely to FMD (r = –0.33, p < 0.005) but not to NTG (r = 0.06, p = 0.60). This association remained significant after adjusting for gender (p = 0.002). In addition, subjects with small apo(a) size of  22 kringle 4 repeats had significantly lower FMD than those with large apo(a) (2.23 ± 2.37% vs. 6.26 ± 4.29%, p < 0.0001), irrespective of Lp(a) levels.
CONCLUSIONS: These findings support an independent role of Lp(a) in atherogenesis, an effect that is particularly evident in African Americans. The proatherogenic property of Lp(a) can be attributed in part to its apo(a) component.
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Abbreviations and Acronyms
| | apo(a) | = apolipoprotein(a) | | FMD | = flow-mediated dilation | | HDL | = high-density lipoprotein | | K4 | = kringle 4 | | LDL | = low-density lipoprotein | | Lp(a) | = lipoprotein(a) | | NTG | = nitrate-induced dilation |
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Lipoprotein(a), or Lp(a), is composed of a cholesterol-rich particle linked to a glycoprotein of variable size called apolipoprotein(a), or apo(a). High levels of Lp(a) have been shown to be a risk factor for cardiovascular disease (1). Epidemiologic studies conducted in Caucasian populations found Lp(a) levels of above 30 mg/dl to increase risk by a factor of two to three. However, recent prospective studies have not been entirely consistent in this regard (2–4). Moreover, a similar risk association was not observed in African Americans (5,6). This latter observation is particularly puzzling given that African Americans tend to have higher Lp(a) levels than Caucasians (7). Because of these inconsistencies, the pathogenic role of Lp(a) remains uncertain.
The Lp(a) level is determined primarily by the apo(a) gene, which varies in size according to the copies of kringle 4 (K4) domains. In Caucasians, Lp(a) levels correlate negatively with apo(a) size, and K4 of <22 copies have been shown to be associated with coronary artery disease (8–10). On the other hand, Lp(a) levels tend to correlate less closely with apo(a) sizes in African Americans (11,12). This difference in size/level correlation among ethnic groups allows for a unique opportunity to delineate the relative contribution of these factors to the atherogenic process.
Accordingly, this study assessed the relationship of Lp(a) levels and apo(a) sizes to endothelial function in a multiethnic cohort free of traditional cardiac risk factors. Endothelial dysfunction is an early and crucial event in atherogenesis (13). Endothelium-dependent flow-mediated dilation (FMD) of the brachial artery has been demonstrated to be impaired in asymptomatic subjects with various established risk factors including those with hypercholesterolemia (14,15). Because endothelial dysfunction occurs at a preclinical stage of disease, its presence serves as a highly sensitive disease marker that may help clarify the pathogenic role of Lp(a) and apo(a) in various ethnic groups.
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Methods
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Study population.
Healthy volunteers were randomly recruited by poster advertisement from the community served by Columbia Presbyterian Medical Center. Subjects underwent a standardized interview and physical examination. Those with evidence of coronary artery disease by symptoms or signs, or with hypercholesterolemia (LDL >160 mg/dl), hypertension (blood pressure [BP] >140/90 mm Hg), diabetes mellitus (fasting glucose >125 mg/dl), or cigarette smoking were excluded. The study protocol was approved by the institutional review board, and all participants gave informed consent.
Lp(a) and apo(a) determination.
Lipoprotein(a) levels were measured by using an enzyme-linked immunoassay insensitive to size variation in apo(a) (Sigma Diagnostics, St. Louis, Missouri). The apo(a) isoform sizes were analyzed by SDS-agarose gel electrophoresis followed by immunoblotting (16). Briefly, 12.5 µl of plasma was mixed with 30 µl of sample buffer, and 10 µl of the mixture was loaded on a 2% submarine agarose gel. Samples were separated for 15 h at 100 V at 4°C using 45 mM Tris-borate buffer, pH 8.6, containing 2 mM EDTA. Proteins were transferred onto nitrocellulose (Amersham Hybond-C extra, Arlington Heights, Illinois) using an electroblotter for 8 h in the cold. The nitrocellulose membrane is blocked using powdered skim milk and then incubated with a primary antibody against apo(a) (Incstar, Stillwater, Minnesota). The apo(a) bands were visualized with the ECL Amersham technique on Kodak X-OMAT films using a second, labeled antibody (Pierce, Rockford, Illinois). Apolipoprotein(a) size was assigned based on the number of K4 repeats of the quantitatively dominant allele and was considered as "small" or "large" using a cutoff point of 22 K4 repeats (8–10). For heterozygotes with two alleles of equal intensity, apo(a) size was assigned to the smaller of the two isoforms. Subjects lacking a detectable allele were excluded.
Assessment of vascular function.
Endothelial and smooth muscle function of the brachial arteries were assessed using a 10-MHz linear array ultrasound transducer (Agilent 5500, Andover, Massachusetts). The vessel was imaged above the antecubital fossa in the longitudinal plane. Flow-mediated dilation was measured as the dilator response to reactive hyperemia induced by inflation of a BP cuff to suprasystolic level ( 300 mm Hg) on the forearm for 5 min. End-diastolic images were acquired every 3 s for 90 s before and after cuff deflation. Smooth muscle dilation was tested by 400 µg of sublingual nitroglycerin followed by imaging at 3 min after oral absorption. Vascular reactivity was measured by two observers blinded to the clinical details of the study subjects. Arterial diameter was determined using automatic edge detection software (Information Integrity, Stowe, Massachusetts). Five consecutive diameter measurements were taken 60 s after cuff deflation for FMD and 4 min after nitrate-induced dilation (NTG). Values obtained by the two observers were averaged and expressed as a percentage change in vessel diameter from baseline. The interobserver variability for FMD was 2.1% based on a sample of 10 subjects.
Statistics.
The relationship of Lp(a) levels and apo(a) sizes to vascular function was assessed as dichotomous as well as continuous variables. Differences among ethnic groups for continuous variables were analyzed by analysis of variance with post-hoc tests using Tukey's procedure. Gender differences were assessed by chi-square analysis. Univariate analysis of the effect of each potential risk factor on FMD and NTG was first performed by linear regression for age, gender, LDL-cholesterol, high-density lipoprotein (HDL) cholesterol, logarithmically transformed triglycerides, systolic BP, and fasting glucose levels for each ethnic group. Similar analysis was also performed for the entire cohort after differences in correlation coefficients among ethnic groups were tested using Fisher z transform followed by a Tukey-type test of differences in the transformed variables. The association between FMD and Lp(a) levels and between FMD and apo(a) sizes adjusted for other risk factors were examined using multiple regression. Only variables that were significant by univariate analysis were entered into the multivariate model. To test for differences in the effect of Lp(a) and apo(a) on FMD among race-ethnic groups, interaction terms were added to the multivariate models using indicator variables that quantified differences in the slope terms between Caucasians and African Americans and between Caucasians and Hispanics. Analysis of variance was performed to jointly test the effect of Lp(a) levels (low vs. high) and apo(a) sizes (small vs. large) on FMD and on NTG.
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Results
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Subjects.
A total of 89 subjects (age 42 ± 9 years; 50 men, 39 women) comprised of 40 Caucasians, 28 African Americans, and 21 Hispanics were recruited (Table 1). All subjects had normal lipoprotein profiles, BPs, and fasting glucose levels. Lipoprotein(a) levels were found to be lowest in Caucasians, intermediate in Hispanics, and highest in American Americans.
Correlation of risk factors with endothelial function.
Univariate analysis within each ethnic group revealed nonsignificant correlation between FMD and various risk factors. The correlation coefficient (r) between Lp(a) and FMD was 0.01 among Caucasians, –0.44 among African Americans, and –0.46 among Hispanics; and for apo(a) and FMD, r was 0.30, 0.44, and 0.10, respectively. When analysis was performed for the entire cohort, significant correlation was found with gender, baseline vessel diameter, Lp(a) level, and apo(a) size (Table 2). In this population without known risk factors, total cholesterol, LDL, HDL, triglycerides, BP, and glucose did not correlate with FMD. Correlation analysis was also performed with absolute vessel dilation, which yielded similar results as FMD with significance for Lp(a), apo(a), and gender (data not shown). In addition, neither Lp(a) levels (r = 0.06, p = 0.55) nor apo(a) sizes (r = 0.01, p = 0.94) related significantly with baseline vessel diameter.
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Table 2 Univariate Correlation Coefficients for Various Risk Factors and Endothelium-Dependent, Flow-Mediated Dilation
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As expected, Lp(a) levels correlated with apo(a) sizes in our cohort (r = –0.52, p < 0.05). Given the known inverse relationship between Lp(a) levels and apo(a) sizes, multiple regression analysis was performed separately for each of these factors. In each of these analyses, Lp(a) and apo(a) were found to correlate significantly with FMD after adjusting for gender (r = –0.33, p = 0.002, and r = 0.34, p = 0.001, respectively) (Figs. 1 and 2). (Although baseline vessel diameter correlated with FMD in univariate analysis, this parameter was not included in the multivariate model because its numerical correlation with FMD may mask important biological associations.) In addition, the relationship of Lp(a) levels to FMD was stronger in African Americans than in Caucasians (p < 0.05). No significant difference in this relationship was observed between Hispanics and Caucasians (p = 0.31). A similar trend was observed for apo(a) on FMD between African Americans and Caucasians (p = 0.11) but not between Hispanics and Caucasians (p = 0.85). No relationship was found between either Lp(a) and NTG (r = 0.06, p = 0.60) or apo(a) and NTG (r = –0.13, p = 0.25).
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Figure 1 Scatterplot of lipoprotein(a), or Lp(a), levels and flow-mediated dilation (FMD) showing a significant inverse correlation. Open diamonds = Caucasians; solid squares = African Americans; open triangles = Hispanics. r = –0.33; p < 0.005.
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Figure 2 Scatterplot of apolipoprotein(a), or apo(a), sizes and flow-mediated dilation (FMD). Open diamonds = Caucasians; solid squares = African Americans; open triangles = Hispanics.
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Interaction of Lp(a) and apo(a) on endothelial function.
To examine the interaction between Lp(a) and apo(a) on endothelial function, subgroup analyses were performed with subjects stratified according to a cutoff point of 30 mg/dl for Lp(a) level and 22 K4 repeats for apo(a) size. Subjects with high Lp(a) levels were found to have significantly lower degree of FMD than those with low Lp(a) levels (3.90 ± 3.58% vs. 6.22 ± 4.47%, p = 0.01). Similarly, those with 22 K4 repeats had significantly lower FMD than subjects with >22 K4 (2.23 ± 2.37% vs. 6.26 ± 4.29%, p < 0.0001). Analysis of variance was then performed with subjects who were divided into four groups based on both Lp(a) level and apo(a) size (Fig. 3). Flow-mediated dilation was relatively preserved with apo(a) sizes >22 K4 (groups A and B), even when they were associated with high Lp(a) levels (group B). When apo(a) sizes were 22 K4, FMD was markedly reduced (groups C and D), despite having Lp(a) levels that were low (group C). The apo(a) size effect was statistically significant (p < 0.001). Similar analyses were performed for NTG, but no differences were found between subjects with high and low Lp(a) (18.97 ± 7.65% vs. 19.80 ± 7.55%, p = 0.05) or between subjects with small and large apo(a) (18.65 ± 8.98% vs. 19.96 ± 8.29%, p = 0.54).
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Figure 3 Endothelium-dependent flow-mediated dilation (FMD) according to four categories based on low and high lipoprotein(a), or Lp(a), levels (cutoff, 30 mg/dl) with small and large apolipoprotein(a), or apo(a), sizes (cutoff, 22 kringle 4 repeats). n indicates number of subjects in each category. *p < 0.001 between small and large apo(a) size groups.
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Discussion
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The present study found high levels of Lp(a) to be independently associated with impaired endothelial function in a multiethnic cohort. Because of inconsistencies in epidemiologic data, the independent role of Lp(a) in cardiovascular disease has been questioned. One possible explanation of Lp(a)'s link to atherosclerosis is through its potentiation of other risk factors, such as LDL cholesterol. By excluding subjects with established cardiac risk factors, we were able to demonstrate a significant independent effect of Lp(a) on endothelial function. The effect of Lp(a) was found to be modest in degree with each 10 mg/dl increment in levels accounting for only 0.4% decrement in FMD. However, because the study cohort was relatively young, the observed magnitude may not be truly reflective of the effect of Lp(a). It remains possible that the effect of Lp(a) might be further amplified through interaction with other risk factors.
The results of this study add to the sum of evidence that indicates that high levels of Lp(a) are associated with preclinical markers of atherosclerotic disease. Previously, several studies have found Lp(a) to be related to early structural changes of the carotid arteries as measured by intima-media thickness (10,17,18). The present study extends these abnormalities to include a functional defect of the vasculature related to Lp(a). These observations seem to differ from those recently reported by Raitakari et al. (19). Using similar methodology, these investigators found Lp(a) levels not to correlate with either FMD or with carotid intimal-medial disease. An in-depth comparison of the two studies is revealing. In contrast with our multiethnic cohort, the latter study was comprised exclusively of Caucasian subjects whose Lp(a) levels were comparatively low (mean of 18.3 vs. 38.7 mg/dl). In our study, significant impairment in FMD was observed only at Lp(a) levels well above 30 mg/dl (Fig. 1). Only a small percentage of subjects (19%) in the Raitakari et al. (19) study have Lp(a) above this level in contrast with 39% of our subjects. Furthermore, the majority of our subjects (80%) with Lp(a) levels above 30 g/dl were of non-Caucasian descent, of whom 63% were African Americans and 17% were Hispanics. Thus, the relationship between Lp(a) and FMD was evident in our study because non-Caucasian subjects were included in the overall analysis. Indeed, on closer examination, the data on Caucasian subjects was remarkably similar in the two studies. These results suggest that the paradox of a lack of disease association with Lp(a) levels in African Americans may be explained by methodological factors rather than on mechanistic grounds.
Apart from Lp(a) levels, apo(a) sizes were also found to have a significant negative effect on endothelial function. As shown in Figure 3, the presence of just one predominant isoform of small apo(a) was associated with markedly reduced FMD. This effect holds true even when the corresponding Lp(a) levels were low (group C). Thus, our analysis revealed that consideration of apo(a) size enhances the ability to predict impaired endothelial function. The modest difference in FMD between subjects with low and high Lp(a) levels was magnified when apo(a) sizes were considered (Fig. 3) (group A vs. C and group B vs. D). The approach of taking into account apo(a) size in risk stratification may be especially important in African Americans in whom Lp(a) levels correlate less closely with apo(a) sizes (11,12).
Our results pointing to a proatherogenic potential of apo(a) is supported by recent experimental evidence. The apo(a) components have been shown to be critical in the initiation of atherogenesis via induction of chemotactic activity to circulating monocytes (20,21), enhancement of expression of intercellular adhesion molecule-1 (22), and promotion of lipid uptake by macrophages (23). Thus, in addition to its effect on Lp(a) level, apo(a) itself appears to exert direct effects on atherogenesis. Although small apo(a) sizes have previously been shown to enhance prothrombotic potential of Lp(a) (24,25), our study substantiates in vivo that apo(a) size variation may confer atherogenic properties (26). Further studies are needed to delineate the precise mechanism by which apo(a) size heterogeneity predispose to atherosclerosis.
This study has several limitations. Although a negative correlation between Lp(a) and FMD was observed across all ethnic groups, we lacked the power to demonstrate statistical significance within each group. Further studies in larger populations are needed to address this point. Another limitation relates to the uncertain prognostic significance of impaired endothelial function of the peripheral circulation as a predictor of adverse cardiovascular outcome. Although endothelial dysfunction of the coronary circulation has been shown to be predictive of adverse cardiac events, the effect of peripheral endothelial dysfunction has yet been conclusively demonstrated. Nevertheless, impaired endothelial function in the brachial artery has been shown to be reflective of the functional state of the coronary endothelium (27) and to correlate with the extent and severity of coronary atherosclerosis (28). Finally, the cross-sectional nature of this study precludes definitive demonstration of a causal relationship between Lp(a) and endothelial dysfunction. Because apo(a) phenotype and Lp(a) level are both under genetic control, their association with endothelial dysfunction is likely primary in nature rather than secondary to subclinical disease.
In conclusion, the present study supports an independent role of Lp(a) in atherogenesis, an effect that is not limited to Caucasians but is particularly evident in African Americans. In addition, consideration of apo(a) size will likely refine our ability to assess an individual's cardiovascular risk. Together, these findings give impetus to conducting large-scale prospective studies to evaluate the risk associated with both Lp(a) levels and apo(a) sizes in different ethnic populations.
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Footnotes
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Supported by a Clinical Associate Physician Award from the NIH (M01 RR00645) and a Pilot Grant from Columbia University to Dr. Wu and an NIH grant (HL 62705) to Dr. Berglund.
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Abstract
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