Lipoprotein(a) associated with coronary artery disease in older women: age and gender analysis

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1 Atherosclerosis 153 (2000) Lipoprotein(a) associated with coronary artery disease in older women: age and gender analysis JoAnne Micale Foody a, John A. Milberg b, Gregory L. Pearce b, Dennis L. Sprecher a, * a Department of Cardiology, The Section of Pre enti e Cardiology and Cardiac Rehabilitation, The Cle eland Clinic Foundation, 9500 Euclid A enue, Cle eland, OH 44195, USA b Department of Biostatistics and Epidemiology, The Cle eland Clinic Foundation, 9500 Euclid A enue, Cle eland, OH 44195, USA Received 23 July 1999; received in revised form 4 January 2000; accepted 14 February 2000 Abstract Background: Lipoprotein (a) has been associated with increased coronary artery disease (CAD) risk in men, but relatively little data exists in women. While age influences the cardiovascular risk associated with Lp(a) in men, little is known about this phenomenon in women. The impact of gender on Lp(a) has not been fully studied in an ongoing clinical practice. Methods and Results: Baseline Lp(a) values were measured in 918 CAD and 829 non-cad patients (603 females, 1144 males) entering an outpatient prevention clinic. The age-specific association of elevated Lp(a) ( 30 mg/dl) with CAD was examined after adjustment for traditional risk factors. Lp(a) was a significant risk factor (OR=1.9, CI, ) in men and women (OR=1.9, CI ). In men age 55 years the odds ratio for increased cardiovascular risk in high vs low Lp(a) was 2.5 (CI ). In men 55, CAD increased from 32 to 61% as Lp(a) progressively rose from 5 to 45 mg/dl (P value for trend 0.001). No significant increase was observed in men 55 years (OR=1.3, CI ). In women 55 years, the risk of CAD increased from 22 to 35% (OR 1.6, CI ), and increased from 38 to 63% in women 55 (OR 2.1, CI ). Further, of high-risk patients (men 55 and women 55 years) with an Lp(a) in the range of 20 44mg/dl (third quartile), younger men showed a greater incidence of CAD (51%) than older women (43%). Both genders revealed substantial risk when the Lp(a) values were above 45 mg/dl. (OR=3.7,CI= in younger men; OR=3.3,CI= in older women). Conclusions: In this cross sectional study of both men and women, elevated Lp(a) was associated with a significantly increased risk of CAD in men and women. While we corroborate previous reports on the lack of association in older men, the determination of an enhanced Lp(a)-related risk in older women was new and unanticipated. Further, in this population of high risk patients, substantial cardiovascular risk appeared to be represented by higher concentrations of Lp(a) in women than observed in men Elsevier Science Ireland Ltd. All rights reserved. Keywords: Lipoproteins; Lipids; Coronary disease; Women; Risk factors 1. Introduction Lipoprotein(a) or Lp(a) is a unique cholesterol-ester rich lipoprotein first isolated in serum in the early 1960s [1]. Lp(a) is similar to LDL but contains an additional glycosylated protein termed apolipoprotein(a). A number of clinical studies, many cross-sectional and/or retrospective in design, have found elevated Lp(a) to be a strong, independent risk factor for coronary artery * Corresponding author. Tel.: ; fax: address: sprechd@ccf.org (D.L. Sprecher). disease (CAD) [2 9]. While three prospective trials have demonstrated a positive association between Lp(a) and CAD [10 12], two large prospective, nested casecontrol studies found little or no influence of elevated baseline Lp(a) levels on subsequent risk of a fatal or non-fatal cardiac event [13,14]. Differences in Lp(a) assay, serum storage techniques, and types of patients studied may account for these discrepancies. In some studies, the effect of Lp(a) on cardiovascular risk differed by age and gender [3,5,6,8,9]. It has been proposed that an increased concentration of Lp(a) may be associated with a more /00/$ - see front matter 2000 Elsevier Science Ireland Ltd. All rights reserved. PII: S (00)

2 446 J.M. Foody et al. / Atherosclerosis 153 (2000) dramatic, progressive increment in cardiovascular risk in women than in men [15]. However, the availability of data particularly in post-menopausal women remains sparse [8,9,16]. The present cross-sectional study sought to examine the effect of Lp(a) on cardiovascular risk and whether this effect was modified by age, gender and Lp(a) concentration in a large, high risk out-patient preventive cardiology clinical practice. 2. Methods Patients were referred to the Cleveland Clinic Foundation (CCF) Preventive Cardiology and Rehabilitation Program (PCRP) in 1996 and 1998 with known CAD as well as without known CAD but who were considered high-risk (non-cad control group). The PCRP is a large referral clinic that seeks to reduce the risk of a first cardiac event or its recurrence (primary and secondary prevention). The clinic sees approximately 50 new patients per month. The majority of patients with a history of CAD are referred from cardiologists or internists at CCF. Onethird of our cohort is referred from outside the hospital. Demographic, general medical and cardiovascular disease history are initially obtained by patient self-report. When available, this information is verified in the hospital or medical chart. Self-reported cardiovascular disease history was validated via the CCF Cardiovascular Interventional Registry (CVIR) [17] and PCRP patient registry for 1996 and The remaining patients classified with CAD in were referred from outside institutions or physicians. The presence of CAD (catheterization indicating greater than 50% stenosis, documentation of MI {EKG, enzymes} and/or positive non-invasive test) in these cases was determined by either medical chart review or patient self-report. Patients without known CAD are referred for a variety of reasons, including family history of CAD, high cholesterol levels, hypertension, obesity and/or smoking habits. Lack of symptoms and absence of a past cardiac history, along with a normal physical examination, permitted entry into this control group. In a significant but small ( 25%) subgroup, cardiovascular diagnostic information (e.g. catheterization reports, or functional tests) was evaluated to corroborate this control status. This overall study population is replete with Framingham risk, including cigarette use, hypertension, diabetes, and enhanced BMI. While more typically observed in CAD populations alone, our control population also is high risk and drawn from the same patient pool as that of the CAD cohort. This setting enhances the comparability of global risk between groups, outside of Lp(a). Therefore, our specific aim is to examine the incremental value of Lp(a) in predicting the presence of CAD when the traditional assessment of cardiovascular risk is high, which is representative of a preventive cardiology practice. Usage of drugs which impact Lp(a) (i.e. niacin and fibrates) constituted less than 30 patients, and exclusion did not alter results. Estrogen use was recorded and entered into the analyses. A total of 75% of cases and a similar proportion of the controls reside in Cuyahoga County in northeast Ohio; an additional 15% are from other parts of the State, while the remaining 10% are split between domestic and international. A total of 8% of the population were non-caucasians, and CAD was distributed similarly between races (59% blacks, 53% white, P= 0.11). The results with and without their inclusion did not change overall results. 3. Data collection All patients are seen in the PCRP Clinic and undergo a standard clinical examination by nurses and physicians which includes: anthropometry (height, weight, waist/hip), blood pressure, and a blood draw for a lipid profile. Height was measured using a stadiometer. Patients also receive dietary and smoking counseling, if necessary. Although patients are typically followed-up every 3 6 months, measurements for this analysis are taken from the baseline evaluation only. Individuals also complete a questionnaire which incorporates numerous risk related issues, including a history of hypertension, family history, cholesterol medication use and diabetes (ever treated, diagnosed by a physician), and in women, menopausal status and use of hormones. 4. Lipid levels and lipoprotein(a) assay Lipoproteins were measured in serum after a 12 h fast in our hospital based Centers for Disease Control and Prevention (CDC) standardized laboratory according to LRC methodology [18]. All samples with triglyceride values above 400 mg/dl were analyzed by beta-quantification. Lp(a) measurements were performed in our hospital chemistry laboratory, utilizing methodology of Incstar Company (Stillwater, Minnesota) according to the package insert. Briefly, this is an automated immunoprecipitan procedure, using monospecific goat antibody to Lp(a). The coefficient of variation is 13% at levels less than 10 mg/dl and 2.5% at levels greater than 60 mg/dl. Values less than 5 mg/dl are undetectable. Lp(a) is known to transiently increase after myocardial infarction [19], however, Lp(a) levels return to baseline levels within 1 month [20]. In our patients, the median time between a coronary event and presentation to our clinic was 10 months.

3 J.M. Foody et al. / Atherosclerosis 153 (2000) Statistical analysis Demographic and clinical features of the CAD and non-cad patients were compared by standard chisquare and t-tests of means. Lp(a) was examined as a dichotomous measure ( 30 mg/dl vs 30) and further by quartile grouping ( 5, 6 19, 20 44, 45 mg/dl). For this analysis, all higher levels were compared to the lowest quartile ( 5 mg/dl). The 30 mg/dl cutoff was selected in order to enable comparison with many previous studies (30 mg/dl represents the 66th percentile in our control population). Similarly, for ease of comparison with previous reports, we stratified the population by age less than or equal to and greater than 55 years (the mean age of our population=57 years.) Multivariable logistic regression was used to assess the impact of Lp(a) on CAD risk. All models were performed separately for men and women. The following risk factors for CAD were included in all models: Age (continuous or grouped as above); Smoking status (ever vs never smoker); Body mass index (kg/m 2 ); selfreported history of diabetes (yes/no); systolic blood pressure; LDL-cholesterol (natural logarithm transformation); and HDL-c (natural logarithm transformation). Lipid-lowering medications at entry use was also included (yes vs no). Menopausal status in women less than 55 years as well as hormone use after the age of 55 years was incorporated into a separate model. We used the Hosmer-Lemeshow statistic to assess the fit of our logistic regression models [21]. 6. Results 6.1. Patient population Between 1996 and 1998, 918 CAD cases and 829 non-cad controls greater than 20 years of age with baseline Lp(a) values were available for analysis. Comparison of the main demographic and clinical features of our population shows that CAD cases are predominantly male (75%) and, in both genders, 8 9 years older than their non-cad counterparts (Table 1). Similarly, in males and females, CAD cases more often reported a history of smoking, hypertension and diabetes. In females, a history of diabetes was reported over two times more frequently in CAD cases than controls (29 vs 12%) Lipid alues Non-CAD patients had significantly higher levels of total cholesterol, LDL-cholesterol, and triglycerides (all P 0.01, Table 2), reflecting a high-risk primary pre- Table 1 CCF Preventive Cardiology Clinic: baseline characteristics Variable Non-CAD (n=457) CAD (n=687) Non-CAD (n=372) CAD (n=231) Age, years (S.D.) 50 (12) 59 (11) 54 (12) 62 (10) Age 55 years n (%) 307 (67) 249 (36) 197 (53) 69 (30) BMI (kg/m 2 ) (S.D.) 28.9 (4.9) 28.8 (4.5) 27.9 (5.8) 29.5 (6.3) Ever smoked (%)* Systolic BP, mm Hg (S.D.) 131 (18) 132 (20) 133 (22) 139 (25) Lipid lowering medications (%) Hypertension (%) Diabetes (%) Table 2 CCF Preventive Cardiology Clinic: median plasma lipid levels at baseline a Variable (mg/dl) Non-CAD CAD Non-CAD CAD Total cholesterol (25 75th percentile) 233 ( ) 203 ( )* 254 ( ) 233 ( ) HDL-cholesterol 38 (31 46) 38 (32 45) 50 (41 60) 45 (37 54) Cholesterol/HDL ratio 6.2 ( ) 5.4 ( ) 5.0 ( ) 5.2 ( ) LDL-cholesterol 141 ( ) 124 (97 151)* 156 ( ) 139 ( ) Triglycerides 218 ( ) 164 ( )* 178 ( ) 182 ( ) Lp(a) 14 ( 5 32) 22 (7 44)* 20 (5 43) 35 (11 64)* Lp(a) 30 mg/dl (%) 27 40* 37 52* a *P 0.05, CAD vs Non-CAD.

4 448 J.M. Foody et al. / Atherosclerosis 153 (2000) Table 3 Median lipoprotein(a) levels by gender, age, and CAD status Age (years) Non-CAD (mg/dl) CAD (mg/dl) Non-CAD (mg/dl) CAD (mg/dl) vention population. A higher proportion of CAD patients were taking lipid-lowering medications at entry (38 vs 19% P 0.01). However, even when patients with lipid lowering medications were excluded, total cholesterol, LDL-C and triglycerides were still higher in the non-cad group (data not shown). HDL-cholesterol values were lower in both male and female CAD patients. Median Lp(a) values were significantly higher in the CAD cases, particularly among females. The overall percent distribution of Lp(a) levels in CAD cases and controls shows the expected non-normal leftskewed distribution of this lipoprotein, and the generally higher values among CAD patients (Table 2) Lp(a) by gender and age Lp(a) values were typically higher in women than men, both at all ages (P 0.01), and in those with and without CAD (P=0.06) (Table 3). had significantly higher serum Lp(a) values than males in non- CAD patients less than 55 years of age (P=0.002) and in patients 55 years and older with CAD (P 0.001) (Table 3). In males with CAD, Lp(a) levels were particularly elevated in the youngest age group examined (20 39 years). The median Lp(a) in this age was about twice as high as men in this age group without CAD (P 0.01). This high Lp(a) spike in the younger CAD male patients was the same level we detected in the oldest group of CAD women, namely those and years of age. We found the strongest association between elevated Lp(a) and increased risk of CAD in these two groups: younger males and older females CV risk of Lp(a) in males Overall, men with elevated Lp(a) had an increase in risk for CAD (OR 1.9, 95% CI ) (Table 4). Men with an elevated Lp(a) 30 mg/dl and who were less than 55 years of age were at greatest risk of CAD (Table 5). Compared to men in this age with an Lp(a) less than 30 mg/dl, patients with a high Lp(a) had nearly a 2.5-fold increased risk of CAD (OR=2.5, 95% CI= ). Adjustment for smoking, diabetes, BMI, LDL-C, HDL-C, systolic blood pressure and lipid lowering drugs did not affect this strong association. However, in all older age groups, elevated Lp(a) was not associated with the risk of CAD in men (Table 4). In males less than 55 years of age, the relative odds of CAD were progressively increased with each successive Lp(a) quartile (compared to patients with Lp(a) 5 mg/dl). The proportion of patients with CAD was 32% in the lowest and 61% in the highest Lp(a) quartile. There was no trend of increasing relative risk of CAD with higher Lp(a) values in the men older than 55 years CV risk of serum Lp(a) concentration in females In women younger than 55 years of age, we detected only a slight increase in risk of CAD with an Lp(a) 30 mg/dl (OR=1.6, 95% CI= ), and somewhat more notable increase at the highest vs lowest quartile (OR=2.1, 95% CI= ) (Table 6). In women over 55 years, however, we detected a 2-fold increased risk of CAD comparing those with serum Lp(a) 30 vs 30 mg/dl (OR=2.1, 95% CI= ). This increased risk of CAD in the older female cohort was isolated to patients in the highest quartile of Lp(a) (OR=3.3, CI= ) (Table 6). Adjustment in the model for hormone use, in addition to the other CAD risk factors, did not effect these results. Table 4 Multivariable Lp(a)/CAD odds ratios (95% CI) by gender and age a Group Total population 55 years 55 years 1.9 ( ) 1.9 ( ) 2.5 ( ) 1.6 ( ) 1.3 ( ) 2.1 ( ) a CAD odds ratio in patients with high vs low Lp(a) ( 30 vs 30 mg/dl), adjusted for age, smoking, diabetes, LDL-c, HDL-c, systolic blood pressure, BMI, and use of lipid-lowering medications at baseline.

5 J.M. Foody et al. / Atherosclerosis 153 (2000) Table 5 CAD prevalence and CAD odds ratio in males by age and Lp(a) level a Age group Value Lp(a) (mg/dl) 5 b years Total no CAD (%) Odds ratio (95% CI) ( ) ( ) ( ) 55+ years Total no CAD (%) Odds ratio (95% CI) ( ) ( ) ( ) a CAD odds ratio in patients with high vs low Lp(a) ( 30 vs 30 mg/dl), adjusted for age, smoking, diabetes, LDL-c, HDL-c, systolic blood pressure, BMI, and use of lipid-lowering medications at baseline. b Reference group. Table 6 CAD prevalence and CAD odds ratio in females by age and Lp(a) level a Age group Value Lp(a) (mg/dl) 5 b years Total no CAD (%) Odds ratio (95% CI) ( ) ( ) ( ) 55+ years Total no CAD (%) Odds ratio (95% CI) ( ) ( ) ( ) a CAD odds ratio in patients with high vs low Lp(a) ( 30 vs 30 mg/dl), adjusted for age, smoking, diabetes, LDL-c, HDL-c, systolic blood pressure, BMI, and use of lipid-lowering medications at baseline. b Reference group Dose-response and model fit The Hosmer-Lemeshow statistic for all gender and age-specific models tested was never significant (P 0.05), indicating good agreement between the observed and expected number of CAD events. Examination of odds ratios by gender for Lp(a) by quartile suggested that CAD risk was associated with Lp(a) above the traditional cutpoint of 30 mg/dl for men, while not as clearly evident in women. The odds ratios were similar for men and women for Lp(a) between 6 and 19 mg/dl. In contrast, younger men showed greater risk (OR= 2.7, CI= ) than older women (OR=1.5, CI= ) in the Lp(a) range between 20 and 39 mg/dl. Both younger men (OR=3.7, CI= ) and older women (OR=3.3, CI= ) showed CAD associated with Lp(a) greater than or equal to 45 mg/dl. 7. Discussion In this cross-sectional study of 1747 male and female patients presenting to a hospital-based preventive cardiology clinic, the effects of elevated Lp(a) on the risk of CAD varied by gender and age. We confirmed the strong, independent effect of lipoprotein(a) values greater than 30 mg/dl on the risk of CAD in men younger than 55 years of age. We present significant new data that supports the value of Lp(a) in defining CV risk in post-menopausal women. Further, in contrast to men, women may have a different risk threshold for Lp(a) regardless of menopausal status. Our data support a number of cross-sectional [2,3,9] and longitudinal [10,16,22] studies showing an increased CAD risk with elevated Lp(a) levels These studies reported stronger effects in younger men, and a diminishing effect of Lp(a) on CAD risk in men older than 55 and 65 years of age. For example, in the Lipid Research Clinic trial, a significant odds ratio of 1.10 [10] was found for Lp(a) 30 mg/dl as a predictor in males with mean age of 47 years, consistent with the Framingham offspring cohort with baseline ages between 20 and 54 years [22] and a 14 year follow-up study of nearly subjects with mean baseline ages

6 450 J.M. Foody et al. / Atherosclerosis 153 (2000) between 40 and 45 years [23], but in contrast to the Physicians Health Study [13] where no association was found between increased Lp(a) and subsequent risk of a cardiac event after follow-up. However, this latter cohort demonstrated a mean age of 59 years. While some disparate results have been found for Lp(a) in the elderly male [16] the apparent absence of Lp(a) influence in older men may reflect a survivor bias where young men with elevated Lp(a) levels are at high risk of early CAD-related mortality [4,5], and other CAD risk factors may predominate in later stages of the lifecycle. In the current study (mean age 57 years, range years), progressively higher Lp(a) values were not related to higher risk in older men, consistent with an odds ratio approaching unity in this subgroup. There are far fewer reported studies on women concerning the relationship between Lp(a) and CAD risk [23,24] and their conclusions are less consistent [9,16]. Utilizing electrophoretic patterns as surrogate markers for Lp(a) values, both the Framingham data [24] (age 55 years) and data from Nguyen [23] (mean age 45 years) suggested predictive value of Lp(a) in women. In contrast, the smaller Stanford Five-City trial [16] did not. Most recently, Sunayama found no statistically significant effect of Lp(a) in women over 50 years of age, but reported significantly elevated odds ratios in the younger women [9], consistent with yet another study in women 60 years of age [7]. In contrast, our study revealed a significant association between Lp(a) and presence of CAD in the entire female cohort, but particularly in those over the age of 55 years. Differences in the distribution of important risk factors for CAD (such as smoking prevalence and lipoprotein levels) between our study population and those reported on previously may contribute to our positive findings in women. More consistent with our findings is the results from one recent study of Swedish women wherein a significant increased risk of CAD (OR= 2.9) in those with Lp(a) levels 30 mg/dl vs those in the lowest quartile of their population ( 6 mg/dl) was observed. This relationship held in both pre and post-menopausal women [8]. Reviews on Lp(a) define the 30 mg/dl level as the cutpoint above which CAD risk is increased, based on data mostly derived from men [3,25 27]. However, in women age 55 years, significant vascular disease has been reported to correspond to Lp(a) values closer to mg/dl [9]. Cross-sectional reports are consistent with this finding [2,28], and the longitudinal risk also appears to contrast between genders; a threshold of 43 mg/dl in women and 33 mg/dl in men in one report [23]. In men and postmenopausal women undergoing CABG surgery with equivalent severity of CAD and virtually identical lipid/ lipoprotein values, 60% of women and only 39% of men had serum Lp(a) values above 25 mg/dl, while aorticbiopsy derived apo(a) was comparatively enriched in the female specimens [29]. This suggests that higher Lp(a) values in women are necessary to impose similar vascular disease to that in men. In the present cohort, using one specific laboratory (noting that Lp(a) measurement standardization remains a goal, not a reality [30]), the predominant risk in women is attributable to values above 50 mg/dl. These data suggest that in our selected cohort, the above 30 mg/ dl cutpoint may be appropriate for men, while some higher threshold value may be more representative of risk in women. Our study is unique in several respects. First, CAD and non-cad patients presented herein represent a very high risk referral group with significant elevations in serum cholesterol concentration and a high prevalence of tobacco use. Our data therefore specifically addresses the incremental value of Lp(a) among subjects with an already high risk profile. Brown et al. [31], in a meta-analysis of predominately male subjects, concludes that the cardiovascular risk associated with Lp(a) is markedly enhanced when LDL-C is elevated. Perhaps our patients represent a group particularly vulnerable to the cardiovascular risk associated with Lp(a). Secondly, our population is diverse and includes both men and women recruited from a similar catchment area. Finally, our data is drawn from an ongoing clinical cardiovascular prevention program where Lp(a) measurements are performed routinely on fresh samples. 8. Conclusion In summary, our cross-sectional analysis of a single, large clinic population corroborates much of the reported data on the significant age and gender differences in the effect of Lp(a) on cardiovascular risk. Further, these are some of the first data to demonstrate a greater Lp(a)-associated risk in older women. In this cohort, cardiovascular disease in women appears to be observed at higher levels of Lp(a) than those in men. References [1] Berg K. A new serum type system in man- the LP-system. Acta Pathol Microbiol Scand 1963;59: [2] Dahlen G, Guyton J, Attar M, Farmer J, Kautz J, Gotto A. Association of levels of lipoprotein Lp(a), plasma lipids, and other lipoproteins with coronary artery disease documented by angiography. Circulation 1986;74: [3] Rhoads G, Dahlen G, Berg K, Morton N, Dannenberg A. 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