The association of microalbuminuria with clinical cardiovascular disease and subclinical atherosclerosis in the elderly: The Cardiovascular Health Study

Atherosclerosis 187 (2006) 372–377

The association of microalbuminuria with clinical cardiovascular disease and subclinical atherosclerosis in the elderly: The Cardiovascular Health Study Jie J. Cao a , Joshua I. Barzilay b , Do Peterson c , Teri A. Manolio a , Bruce M. Psaty d , Lewis Kuller e , Jason Wexler f , Anthony J. Bleyer g , Mary Cushman h,∗ b

a National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA Kaiser Permanente of Georgia and the Division of Endocrinology, Emory University School of Medicine, Atlanta, GA, USA c Department of Biostatistics, University of Washington, Seattle, WA, USA d Departments of Medicine, Epidemiology and Health Services, University of Washington, Seattle, WA, USA e Department of Epidemiology, University of Pittsburgh, PA, USA f Department of Medicine, University of California at Davis, Davis, CA, USA g Department of Medicine, Wake Forest University, Winston-Salem, NC, USA h Departments of Medicine and Pathology, University of Vermont, College of Medicine, Burlington, VT, USA

Received 1 March 2005; received in revised form 31 August 2005; accepted 15 September 2005 Available online 20 October 2005

Abstract Purpose: Microalbuminuria (MA) is a risk factor for cardiovascular disease (CVD). It is not known whether this association is due to the effect of MA on the development of subclinical atherosclerosis or whether MA destabilizes subclinical atherosclerosis, leading to clinical events. Methods: In a cross-sectional analysis we evaluated 3312 Cardiovascular Health Study participants, age ≥65 years, who had MA testing. Participants were divided into three groups: those without diabetes or hypertension (33%), those with hypertension (52%) and those with diabetes, with or without hypertension (15%). Clinical CVD was defined as presence of coronary heart disease (angina, MI, CABG, PTCA), cerebrovascular disease (stroke, TIA) and peripheral arterial disease (requiring intervention). Among those without clinical disease, subclinical atherosclerosis was defined as increased carotid artery intima-media thickness, decreased ankle arm index or increased left ventricular mass. Results: In each of the three groups of participants, the adjusted odds of prevalent clinical CVD in the presence of MA was 1.70–1.80-fold increased, independent of other risk factors. MA was not associated with risk of subclinical atherosclerosis in those without hypertension or diabetes (OR 1.14 [95% CI 0.59, 2.23]), whereas it was associated with subclinical atherosclerosis in those with hypertension (OR 1.58 [95% CI 1.08, 2.30]) or diabetes (OR 2.51 [95% CI 1.27, 4.94]). Conclusion: In the absence of hypertension or diabetes, MA was associated with clinical CVD but not with subclinical atherosclerosis. Thus, a hypothesis may be made that the mechanism of association of MA with clinical vascular disease involves destabilization of the vasculature, leading to clinical disease. © 2005 Elsevier Ireland Ltd. All rights reserved. Keywords: Microalbuminuria; Cardiovascular disease; Hypertension; Diabetes mellitus

1. Introduction ∗

Corresponding author. Present address: University of Vermont, 208 South Park Drive, Suite 2, Colchester, VT 05446, USA. Tel.: +1 802 656 8959; fax: +1 802 656 8965. E-mail address: [email protected] (M. Cushman). 0021-9150/$ – see front matter © 2005 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2005.09.015

Microalbuminuria is a risk factor for clinical cardiovascular disease (CVD) [1–5]. Whether this association represents a causal mechanism is unknown. It is possible that microalbuminuria is related to CVD because it is associated with

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factors such as altered homeostasis in the coagulation system [6,7], increased vascular permeability [6–8] and enhanced inflammatory response [6,18,19] that cause atherosclerosis to destabilize and become clinical disease. Microalbuminuria is most commonly associated with diabetes and hypertension [2,5,7]. Both of these conditions are risk factors for clinical CVD, thereby confounding the relationship of microalbuminuria with clinical CVD. To evaluate the independent effects of microalbuminuria on atherosclerosis and clinical CVD it would be best to examine individuals without diabetes or hypertension. Previous publications have shown microalbuminuria prevalence in the absence of hypertension and diabetes in the general population [4,8,9], but the relationship between microalbuminuria and clinical CVD and subclinical atherosclerosis in the absence of those risk factors is not well defined. The Cardiovascular Health Study (CHS) is a populationbased cohort study of individuals aged ≥65 years that was designed to identify risk factors for CVD in older age. It has accumulated data on CVD risk factors (including microalbuminuria), non-invasively assessed subclinical atherosclerosis and clinical CVD events. Therefore, the differential relationships of microalbuminuria to atherosclerosis and clinical events can be studied in this group. In a previous CHS publication, we noted a high prevalence of microalbuminuria among participants without hypertension or diabetes [6]. In this study we examine the relationship of microalbuminuria with subclinical atherosclerosis and prevalent clinical CVD in participants without diabetes or hypertension, as well as in participants with diabetes or hypertension.

2. Methods The CHS is an observational study of 5888 elderly men and women randomly chosen from Health Care Finance Administration Medicare eligibility lists in four US communities: Forsyth County, NC; Sacramento County, CA; Washington County, MD and Pittsburgh, PA. The study design has been published previously [10]. Between 1989 and 1990, the initial cohort of 5201 participants was enrolled. An additional 687 African American participants were enrolled between 1992 and 1993 using similar methods. All participants provided informed consent on enrolment and at follow-up visits. All participants underwent baseline and subsequent annual clinical examinations. Participants included in this analysis were those who attended the 1996–1997 visit and provided a urine sample at that visit. 2.1. Definitions Prevalent cardiovascular events were assessed based on the presence of clinical events validated by standardized criteria either at baseline or during follow-up through the 1996–1997 visit. Methods of ascertainment of clinical disease have been published [11–13]. Prevalent clinical CVD

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was defined as a previous history of confirmed transient ischemic attack (TIA), stroke, angina, myocardial infarction, coronary revascularization and peripheral artery disease requiring intervention. Prevalent subclinical atherosclerosis was classified as the presence of any of the following in the absence of any manifestation of clinical CVD at the time of the 1996–1997 visit [12]: internal or common carotid intima-media thickness (IMT) > 80th percentile (measured in 1992–1993), ankle arm blood pressure index (ABI) < 0.9 (measured in 1992–1993) and left ventricular mass (LVM) > 80th percentile (measured in 1994–1995). Both hypertension and diabetes status were based on 1996–1997 visit information. Hypertension was defined based on the JNC VII guideline to include individuals with systolic blood pressure greater than 140 mmHg and diastolic blood pressure greater than 90 mmHg or those taking blood pressure medicine. The diagnosis of diabetes mellitus was made following ADA criteria as fasting glucose >125 mg/dL or use of insulin or oral glucose lowering agents. 2.2. Laboratory methods A random morning urine specimen was obtained at the 1996–1997 visit. Urine creatinine and albumin were measured on a Kodak Ektachem 700 Analyzer and Beckman Array 360 CE protein Analyzer (Beckman Instruments, Fullerton, CA), respectively. Microalbuminuria was defined as 30–300 ␮g albumin/mg creatinine [14]. Participants with albuminuria >300 ␮g albumin/mg creatinine (macroalbuminuria) were excluded from the analysis. C-reactive protein (CRP) was measured in the 1994–1995 visit using a BN-II nephelometer (N High Sensitivity CRP; Dade Behring Inc., Deerfield, IL) with a coefficient of variation of 2.1–5.7%. 2.3. Statistical analysis The statistical software SPSS 10.0 was used for all analyses. Pearson’s Chi-square, Wilcoxon–Mann–Whitney ranksum and t-tests were applied to univariate analyses. For analysis of associations of microalbuminuria with clinical CVD and subclinical atherosclerosis, the cohort was divided into three groups based on hypertension and diabetes status: those with neither diabetes nor hypertension, hypertension only and diabetes with or without hypertension. Associations of microalbuminuria with prevalent CVD and subclinical atherosclerosis were assessed using multivariate logistic regression models, taking into account risk factors associated with both microalbuminuria and vascular disease as determined by univariate analyses. Covariates included in multivariate models were urine creatinine, diastolic blood pressure, systolic blood pressure, fasting glucose, hypertension, diabetes mellitus, age, pack-years of smoking, sex, body mass index, HDL, triglyceride and CRP. Interaction terms testing for multiplicative interaction between microalbuminuria and diabetes or hypertension were evalu-

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ated in models for prevalent clinical CVD and subclinical atherosclerosis.

3. Results Among the 4412 participants alive in 1996–1997, 3424 (72.7%) provided a urine sample. Missing urine samples were due to: telephone interview or home visit (63%), inability to participate in follow-up (21%), inability to give urine sample at the time of interview (15%) and other miscellaneous reasons (1%). Those without a urine specimen were older (80.5 ± 5.7 versus 78.0 ± 4.8, p < 0.001) and were more likely to have clinical CVD (43.5% versus 31.7%, p < 0.001) than those who did not provide a urine sample. Of the 3424 participants who provided urine samples, 3% had macroalbuminuria and were excluded from the analysis, and 16% had MA. In Table 1, those with MA were more likely to be older, male, to smoke, to have diabetes, hypertension, higher fasting glucose, CRP, systolic and diastolic blood pressure, triglyceride and lower HDL cholesterol when compared to the group with normal urinary albumin. Of the 3312 indi-

viduals who had complete data for hypertension and diabetes status, 1103 (33.1%) had neither hypertension nor diabetes, 1702 (51.5%) had hypertension only, and 507 (15.4%) had diabetes, with or without hypertension. The prevalence of microalbuminuria in these three groups was 7.8, 16.7 and 31.2%, respectively (Table 2). The odds of any form of clinical CVD being present in those with MA compared to no MA were similar in the three groups of participants (odds ratios 1.71–1.86) (Table 3). There were differences, however, in the association of microalbuminuria with individual types of clinical CVD in groups defined by hypertension and diabetes. Microalbuminuria was most strongly associated with cerebrovascular disease among those without hypertension or diabetes, whereas it was similarly associated with disease in the cerebral, coronary and peripheral vascular systems in participants with hypertension. In those with diabetes, microalbuminuria was most strongly associated with peripheral artery disease. There were pronounced differences in the odds of any form of subclinical atherosclerosis in association with microalbuminuria in the three groups. The odds were not significantly elevated in those without diabetes or hypertension (OR 1.14

Table 1 Participant characteristics with and without microalbuminuria No albuminuria (% or mean ± S.D.) (N = 2769)

Microalbuminuria (% or mean) (N = 551)

p-Value

Age (years) Female gender (%) Caucasian race (%) Hypertension (%) Diabetes mellitus (%)

77.8 ± 4.6 61.7 83.5 58.7 11.5

79.2 ± 5.5 53.4 81.7 77.3 29.8

<0.001 0.003 0.30 <0.001 <0.001

Smoking status Ever (%) Never (%)

43.7 49.3

49.4 40.9

Smoking, pack-years Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Body mass index (kg/m2 ) Fasting glucose (mg/dL) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) HDL cholesterol (mg/dL) Triglyceride (mg/dL) C-reactive protein (mg/L)b

15 ± 23 135 ± 19 70 ± 10 27.0 ± 4.7 99 ± 27 210 ± 38 129 ± 33 54 ± 14 141 ± 80 1.7 (0.9, 3.0)

19 ± 27 145 ± 23 72 ± 12 26.6 ± 4.6 115 ± 43 207 ± 9 126 ± 34 51 ± 14 157 ± 113 2.1 (0.2, 3.7)

a b

0.001 0.006a <0.001 <0.001 0.09 <0.001 0.054 0.165 <0.001 0.001 <0.001a

p-Value from Wilcoxon–Mann–Whitney rank-sum test because of skewed distributions. C-reactive protein was expressed as median and interquartile range.

Table 2 Prevalence of microalbuminuria in the presence or absence of diabetes and/or hypertension Albuminuria status (%) None

Micro

Macro

No HTN/no DM HTN/no DM DM with or without HTNa

1013 (91.8) 1366 (80.3) 307 (60.6)

85 (7.7) 284 (16.7) 158 (31.2)

5 (0.5) 52 (3.0) 42 (8.2)

1103 1702 507

Total number

2686 (81.0)

527 (15.9)

99 (3.1)

3312

a

There were 376 with DM and HTN and 131 with DM but no HTN.

Total number

Table 3 Prevalence and adjusted odds (95% CI)a of clinical and subclinical cardiovascular disease in elderly with and without microalbuminuria categorized by the presence or absence of hypertension and diabetes No hypertension or diabetes (n = 1098) Clinical cardiovascular disease

Subclinical cardiovascular disease

Disease type

MA present (n = 85) (%)

MA absent (n = 1013) (%)

OR (95% CI)

Disease type

MA present (n = 85) (%)

MA absent (n = 1013) (%)

OR (95% CI)

Cerebral disease Coronary disease Peripheral disease

12.8 27.9 1.2

5.3 19.4 2.1

2.47 (1.14, 5.38) 1.40 (0.81, 2.43) –b

IC/CC IMT > 80th percentile LVM > 80th percentile ABI < 0.9

31.4 18. 8 3.9

19.4 11.0 2.4

1.23 (0.61, 2.49) 1.47 (0.49, 4.37) –b

Total

38.4

23.5

1.71 (1.02, 2.86)

Total

37.7

25.8

1.14 (0.59, 2.21)

Clinical cardiovascular disease

Subclinical cardiovascular disease

Disease type

MA present (n = 284) (%)

MA absent (n = 1366) (%)

OR (95% CI)

Disease type

MA present (n = 284) (%)

MA absent (n = 1366) (%)

OR (95% CI)

Cerebral disease Coronary disease Peripheral disease

15.2 33.9 5.7

8.3 21.7 2.3

1.85 (1.21, 2.83) 1.82 (1.33, 2.49) 1.72 (0.85, 3.50)

IC/CC IMT > 80th percentile LVM > 80th percentile ABI < 0.9

36.5 26.1 11.5

29.1 16.5 6.7

1.19 (0.80, 1.75) 1.94 (1.11, 3.41) 1.35 (0.73, 2.47)

Total

42.8

27.7

1.86 (1.39, 2.50)

Total

50.6

37.7

1.58 (1.08, 2.29)

Diabetes with or without Hypertension (n = 465) Clinical cardiovascular disease

Subclinical cardiovascular disease

Disease Type

MA present (n = 158) (%)

MA absent (n = 307)

OR (95% CI)

Disease type

MA present (n = 158) (%)

MA absent (n = 307) (%)

OR (95% CI)

Cerebral disease Coronary disease Peripheral disease

17.2 38.9 8.3

8.1 29.4 1.9

1.16 (0.56, 2.41) 1.80 (1.08, 3.01) 4.04 (1.06, 15.37)

IC/CC IMT > 80th percentile LVM > 80th percentile ABI < 0.9

44.7 23.2 16.4

34.5 25.0 2.1

2.09 (1.07, 4.09) 0.99 (0.35, 2.81) 6.05 (1.61, 22.76)

Total

51.0

34.6

1.73 (1.06, 2.82)

Total

59.7

44.1

2.51 (1.27, 4.94)

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Hypertension (n = 1650)

Abbreviations: MA, microalbuminuria. Among those with MA the following number of participants had at least one clinical CVD: no HTN, no DM, n = 33; HTN, n = 121; DM, n = 80. Among those without MA, the following number of participants had least one clinical CVD: no HTN, no DM, n = 238; HTN, n = 379; DM, n = 107. Among those with MA the following number of participants had at least one form of subclinical CVD: no HTN, no DM, n = 20; HTN, n = 82; DM, n = 46. Among those without MA, the following number of participants had at least one form of subclinical CVD: no HTN, no DM, n = 200; HTN, n = 372; DM, n = 89. a Multivariate models adjusted for urine creatinine, diastolic blood pressure, systolic blood pressure, fasting glucose, hypertension, diabetes mellitus, age, pack-years of smoking, sex, body mass index, HDL, triglyceride and CRP. b Numbers too small for analysis.

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[95% CI 0.59, 2.23]). On the other hand, the odds were moderately elevated in those with hypertension (1.58 [95% CI 1.08, 2.30]) and were even higher in those with diabetes (2.51 [95% CI 1.27, 4.94]). Among those with hypertension, microalbuminuria primarily associated with increased left ventricular mass. Among those with diabetes, the strongest association of microalbuminuria with subclinical atherosclerosis was with low ABI. Interaction terms testing multiplicative interaction between microalbuminuria and diabetes or hypertension were tested in models for clinical CVD and subclinical atherosclerosis. There was no statistical evidence that the joint risks departed from a multiplicative model (p > 0.05).

4. Discussion In this cross-sectional study of adults aged 65 years and older, microalbuminuria was associated with clinical CVD whether or not hypertension or diabetes was present. Among those without clinical CVD, in the absence of hypertension and diabetes, microalbuminuria had little association with subclinical atherosclerosis. Conversely, microalbuminuria was associated with manifestations of subclinical atherosclerosis among those with hypertension or diabetes. Differences in the association of microalbuminuria with subclinical atherosclerosis by hypertension and diabetes status were not statistically significant on the multiplicative scale. Based on these findings a hypothesis may be presented that microalbuminuria, in the absence of hypertension or diabetes does not enhance measurable atherosclerosis. Rather the mechanism underlying an association of microalbuminuria with vascular disease may relate to destabilization of existing atherosclerosis, leading to clinical events. This hypothesis is plausible since microalbuminuria has been detected within minutes and hours of onset of ischemia [15] or myocardial infarction [16,17]. The link between microalbuminuria and vascular instability is also supported by our previous analysis of CHS participants and by other work documenting an association of microalbuminuria with inflammation markers [6,18,19]. Furthermore, the association of microalbuminuria with altered hemostasis might be another important mechanism in the development of clinical vascular disease [20–22]. While there was no association of microalbuminuria with subclinical atherosclerosis in the absence of diabetes or hypertension, we observed a moderate association between microalbuminuria and subclinical vascular disease (primarily increased LV mass) in participants with hypertension, and a strong association in those with diabetes (higher IMT and lower ABI). Studies that have reported a positive association between microalbuminuria and IMT have included people with diabetes [23,24]. Those that have examined people with hypertension (without diabetes) have reported conflicting results [25,26]. In those studies a relationship between microalbuminuria and subclinical vascular disease was not

found after the presence of hypertension was adjusted for. Thus, our findings are consistent with the literature. To our knowledge our study is the first to report an association of microalbuminuria with prevalent clinical CVD in a large population without diabetes or hypertension in which strict diagnostic criteria were applied. A previous report based on a large non-diabetic and non-hypertensive cohort demonstrated a significant association between microalbuminuria and clinical CVD. However, the observation might be biased, since that study included a large number of individuals with untreated hypertension [9]. The strengths of this study include the availability of several different measures of clinical disease and subclinical atherosclerosis to give a broad overview of the association of microalbuminuria with CVD. Some limitations require consideration. First, the study was cross-sectional, so cause and effect cannot be determined. Second, many of the tests were obtained years apart. While this might be considered a limitation, many of the measures should not have changed much in the intervening time periods. Third, microalbuminuria was not measured at baseline, only on follow-up. This could introduce bias since participants who had microalbuminuria at baseline may have died prior to the time of microalbuminuria testing. The prevalence of microalbuminuria was probably high among participants who died before microalbuminuria was measured since a large number of them had hypertension, diabetes and died of cardiovascular causes. Also, microalbuminuria was tested only once, so assay variability could not be minimized [27]. In addition, the impact of medications on microalbuminuria was not assessed. All of these factors would be expected to lead to bias of findings toward the null hypothesis, so the observed associations might underestimate true ones. Finally, the participants were mostly Caucasian and results may not generalize to other ethnic groups. In conclusion, in the absence of hypertension or diabetes, microalbuminuria is significantly associated with clinical CVD, but not with subclinical atherosclerosis. It follows that microalbuminuria may have a role in destabilizing atherosclerosis, leading to clinical vascular events.

Acknowledgments This research was supported by contracts N01-HC-85079 through N01-HC-85086, N01-HC-35129, and N01 HC15103 from the National Heart, Lung and Blood Institute. A full list of participating CHS investigators and institutions can be found at http://www.chs-nhlbi.org.

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