Mild chronic microvessel ischemic white matter disease

J Gerontol A Biol Sci Med Sci. 2014 Dec; 69(12): 1495–1502.

Dae Hyun Kim,

Abstract

Background.

Microvascular and macrovascular abnormalities are frequently found on noninvasive tests performed in older adults. Their prognostic implications on disability and life expectancy have not been collectively assessed.

Methods.

This prospective study included 2,452 adults (mean age: 79.5 years) with available measures of microvascular (brain, retina, kidney) and macrovascular abnormalities (brain, carotid, coronary, peripheral artery) in the Cardiovascular Health Study. The burden of microvascular and macrovascular abnormalities was examined in relation to total, activity-of-daily-living disability-free, and severe disability-free life expectancies in the next 10 years (1999–2009).

Results.

At 75 years, individuals with low burden of both abnormalities lived, on average, 8.71 years (95% confidence interval: 8.29, 9.12) of which 7.67 years (7.16, 8.17) were without disability. In comparison, individuals with high burden of both abnormalities had shortest total life expectancy (6.95 years [6.52, 7.37]; p < .001) and disability-free life expectancy (5.60 years [5.10, 6.11]; p < .001). Although total life expectancy was similarly reduced for those with high burden of either type of abnormalities (microvascular: 7.96 years [7.50, 8.42] vs macrovascular: 8.25 years [7.80, 8.70]; p = .10), microvascular abnormalities seemed to have larger impact than macrovascular abnormalities on disability-free life expectancy (6.45 years [5.90, 6.99] vs 6.96 years [6.43, 7.48]; p = .016). These results were consistent for severe disability-free life expectancy and in individuals without clinical cardiovascular disease.

Conclusions.

Considering both microvascular and macrovascular abnormalities from multiple noninvasive tests may provide additional prognostic information on how older adults spend their remaining life. Optimal clinical use of this information remains to be determined.

Key Words: Cardiovascular, Epidemiology, Longevity, Disablement process.

The evidence of microvascular and macrovascular abnormalities is frequently found on noninvasive tests that are obtained for various clinical indications in older adults. This information is often ignored or not fully appreciated by clinicians, despite several lines of evidence that these abnormalities predict poor outcomes of aging. In previous research, macrovascular abnormalities in the brain, carotid, coronary, and peripheral arteries were associated with frailty, disability, and mortality (1,2). More recently, microvascular abnormalities in the brain (3–5), retina (6–8), and kidney (9,10) have been associated with impairment in cognitive and physical function. However, prior studies attempted to summarize the extent of macrovascular abnormalities without considering microvascular abnormalities (1,2) or examined them separately by each organ (3–10). As considering abnormalities in multiple vascular beds is useful in predicting future disease risk (11), summarizing both microvascular and macrovascular abnormalities collectively may facilitate identifying older adults who are more likely to die or live in disability.

In this study, we analyzed data from the Cardiovascular Health Study (CHS) that has an extensive list of noninvasive tests of microvascular and macrovascular abnormalities from a large number of community-dwelling older adults. We aimed to examine the prognostic implications of microvascular and macrovascular abnormalities in relation to total and disability-free life expectancies (LEs).

Methods

Study Population

The CHS is a prospective cohort study of cardiovascular disease (CVD) in adults aged 65 years or older (12,13). In 1989–1990, 5,201 adults were recruited from four U.S. communities. An additional 687 African Americans were recruited in 1992–1993. In 1996–1999, participants underwent measurements of cystatin C, urinary albumin, retinal photography, electrocardiography, ankle-arm index, carotid ultrasonography, and brain magnetic resonance imaging (Supplementary Method 1). On the basis of these tests, we assessed five measures of microvascular abnormalities in the brain, retina, and kidney and six measures of macrovascular abnormalities in the brain, carotid, coronary, and peripheral arteries. We included 2,452 adults who had data on ≥3 measures of each process. Using the 1998–1999 clinic visit as baseline, participants were followed until December 31, 2009. The institutional review boards at the participating CHS centers and the Beth Israel Deaconess Medical Center, Boston, MA, approved this study.

Quantification of Microvascular and Macrovascular Abnormality Burden

Measures of microvascular abnormalities in the brain, retina, and kidney included the following: white matter hyperintensity, small (3–20mm) brain infarcts, retinal microvascular signs (generalized arteriolar narrowing, generalized venular widening, retinopathy, arteriovenous nicking, and focal arteriolar narrowing), urine albumin-to-creatinine ratio, and cystatin C-based glomerular filtration rate (14). As some evidence suggests that generalized venular widening is a marker of systemic processes (eg, inflammation) rather than structural pathology (15), we also created a microvascular index without generalized venular widening (see later). Measures of macrovascular abnormalities in the brain, carotid, coronary, and peripheral arteries included the following: large (>20mm) brain infarcts, common and internal carotid artery intima-media thickness, carotid artery stenosis, electrocardiographic abnormalities, and ankle-arm index. For each measure, we assigned 0, 1, or 2 for minimal, modest, or moderate-to-severe abnormalities based on cut points that are clinically meaningful or previously associated with poor outcomes (Table 1 and Supplementary Method 1 for detailed description of measurement). Individual scores were aggregated to construct a microvascular index (range: 0–10) and a macrovascular index (0–12).

Table 1.

Quantification of Microvascular and Macrovascular Disease Burden

Assessment of Disability

Disability was assessed by means of semiannual telephone interviews (1999–2009) or annual in-person interviews (2005–2009) in the following six activities of daily living (ADLs): bathing, dressing, eating, toileting, walking around the home, and transferring. Two different versions of ADL questionnaire were used: in 1999–2004, participants were asked about changes in their ability to perform ADLs since the last interview (less, unchanged, or more or new-onset difficulty); in 1998–1999 and 2005–2009, they were asked to quantify the amount of difficulty (no difficulty, some difficulty, a lot of difficulty, or unable to do). Therefore, we had to estimate the amount of difficulty for the 1999–2004 period, using the information on change in ADL difficulty and the amount of difficulty before and after this period (Supplementary Method 2). Because unavailability of data on the amount of difficulty for this period can be considered as missing data by study design, our estimation is unlikely to cause misclassification differentially by exposure groups. At each interview, participants were classified as having disability if they reported any level of difficulty with ≥1 ADL and as having severe disability if they reported a lot of difficulty or unable to perform ≥3 ADLs.

Measurement of Covariates

Questionnaires were used to obtain information on sociodemographic characteristics, alcohol consumption, cigarette smoking, medical history, and physical activity level (kcal/wk) using the modified Minnesota Leisure-Time Activities questionnaire (16). Body mass index (kg/m2) and blood pressure (mmHg) were measured according to standardized protocols (12). Hypertension was defined as blood pressure ≥140/90 mmHg or antihypertensive medication use. Diabetes was defined as the use of either oral hypoglycemic agents or insulin in the year before the examination, or having a fasting glucose ≥126mg/dL for those not using any hypoglycemic agents in the past year. Clinical CVD, including angina pectoris, myocardial infarction, congestive heart failure, peripheral arterial disease, and stroke or transient ischemic attack, were adjudicated based on medical record review by the CHS event committee (17).

Statistical Analysis

All analyses were performed in Stata SE v11.2 (StataCorp, College Station, Texas) and two-sided p < .05 was considered statistically significant. Among 2,452 participants, the amount of missing data varied from 2% (for electrocardiography) to 19% (for gradable retinal photographs for retinal microvascular signs) for vascular measures and was <3% for covariates. We conducted multivariable imputation for all missing data, using sociodemographic characteristics, lifestyle risk factors, comorbidities, measures of vascular abnormalities, functional status, and disability (18).

We compared the characteristics of individuals according to their burden of microvascular and macrovascular abnormalities using analysis of variance, Kruskal-Wallis test, and chi-square test. Individuals were considered as having high burden of microvascular or macrovascular abnormalities if the respective index was greater than the population median. They were classified as having minimal, predominantly microvascular, predominantly macrovascular, and both abnormalities.

In the main analysis, we calculated total remaining LE as the number of years alive during the 10-year follow-up. Disability-free and severe disability-free LEs were calculated as total LE multiplied by the proportion of interviews in which participants were free of any or severe disability, respectively. This approach captures recurrence and recovery of disability (19,20) until death and allows more intuitive interpretation by summarizing the effect of vascular disease in terms of gain (or loss) in the number of years alive with or without disability. We used linear regression and median regression to model the mean and median LE as a function of microvascular index, macrovascular index, and their product term, as well as age (years), sex, white race, education (years), alcohol consumption (≥1 drink/wk or <1), smoking status (never, former, or current), physical activity quintile, and body mass index quintile. We determined the importance of microvascular and macrovascular abnormalities by comparing the difference in LEs between those at 25th percentile and at 75th percentile of each index. Standard errors were estimated from 1,000 bootstrap resampling. The following sensitivity analyses were performed: (a) adjusting for hypertension and diabetes; (b) restricting to those without diabetes; (b) restricting to those without clinical CVD; (d) redefining our microvascular index without generalized arteriolar narrowing or generalized venular widening; and (e) stratifying by age (<80 vs ≥80 years).

Results

In this sample of community-dwelling older adults (mean age 79.5 [standard deviation: 4.3] years, male 40%, white race 84%), the median [interquartile range] was 2 [1, 4] for microvascular index and 5 [3, 7] for macrovascular index. The burden of microvascular and macrovascular abnormalities increased with advancing age (Figure 1). Within each age group, men had higher macrovascular index than women (p < .001). Women had higher microvascular index than men only among those aged <80 years (p = .047).

Distribution of microvascular and macrovascular burden.**

The upper, middle, and lower lines of a box plot correspond to 75th, 50th, and 25th percentile values. The upper and lower whiskers represent the highest and lowest value within 1.5 times of the interquartile range, respectively.

†Microvascular index was lower in males than in females (p < .05).

‡Macrovascular index was higher in males than in females (p < .01).

Compared with individuals with minimal abnormalities, current smoking, hypertension, and diabetes were more common and physical activity was lower in those with high burden of any type of vascular abnormalities; hypercholesterolemia were more common in those with predominantly macrovascular or both abnormalities (Table 2). Despite statistical significance, body mass index did not materially differ across vascular disease categories. Those with predominantly microvascular abnormalities had the prevalence of clinical CVD that was similar to those with minimal abnormalities and lower than those with predominantly macrovascular or both abnormalities.

Table 2.

Characteristics of Participants According to Microvascular and Macrovascular Disease Burden*

During 10 years of follow-up, 1,285 participants died. The mortality was 35% for minimal, 56% for predominantly microvascular, 51% for predominantly macrovascular, and 77% for both abnormalities. After adjusting for potential confounders, those with high burden (75th percentile) of both abnormalities, on average, had shorter total LE, disability-free LE, and severe disability-free LEs than those with low burden (25th percentile) (Table 3). Having high burden of either type of abnormalities was associated with shorter total and disability-free LEs than having low burden of both. Although total LE was not different between the two types of abnormalities (7.96 vs 8.25 years; p = .100), microvascular abnormalities seemed to have a larger impact than macrovascular abnormalities on disability-free LE (6.45 vs 6.96 years; p = .016) and severe disability-free LE (7.78 vs 8.16 years; p = .041). Results were consistent when the median was examined (Table 3). Adjustment for hypertension and diabetes, restriction to those without diabetes or those without clinical CVD, and excluding generalized arteriolar narrowing or venular widening had little effect on these results (data not shown). The difference in total and disability-free LEs across vascular disease categories was similar in stratified analysis by age (<80 or ≥80 years; Supplementary Table).

Table 3.

Total and Disability-Free Remaining Life According to Microvascular and Macrovascular Disease Burden

When the mean duration of disability was examined (Figure 2), individuals with low burden of both abnormalities lived 12.5 months (8.2, 16.8) in disability of which 0.8 months (0.0, 2.1) were in severe disability. In comparison, those with high burden of both abnormalities spent 16.1 months (11.6, 20.6) in disability (p = .015), so did those with high burden of either type of vascular abnormalities (predominantly microvascular: 18.1 months [13.4, 22.9], p = .002; predominantly macrovascular: 15.5 months [11.0, 20.1], p = .036). The duration of severe disability tended to be longer among those with high burden of both abnormalities (2.1 months [0.6, 3.5], p = .036) and those with high burden of microvascular abnormalities (2.1 months [0.5, 3.7], p =.055), but not among those with high burden of macrovascular abnormalities (1.1 months [0.0, 2.6], p = .63).

Total remaining life expectancy and time in disability at 75 years according to microvascular and macrovascular disease burden.*

*The number in the bar graph represents the mean time (months) spent in no disability, mild disability (defined as any difficulty in performing ≥1 activity of daily living, but without severe disability), and severe disability (defined as a lot of difficulty or unable to perform ≥3 activities of daily living) for a 75-year-old white man with 12 years of education, alcohol consumption ≥1 drink/wk, never smoking, physical activity level 555–1,079 kcal/wk, and body mass index 25–28kg/m2.

Discussion

In the community-dwelling older adults, having both microvascular and macrovascular abnormalities was associated with the shortest total and disability-free LEs for the next 10 years. Individuals with high burden of microvascular abnormalities compared with those with high burden of macrovascular abnormalities had lower prevalence of clinical CVD, yet similarly reduced total LE. More importantly, microvascular abnormalities seemed to be associated with shorter disability-free LE and severe disability-free LE than macrovascular abnormalities. Our findings underscore the prognostic importance of considering both microvascular and macrovascular abnormalities in predicting longevity and functional independence in late life.

Microvascular disease can result from arteriolosclerosis, a nonatheromatous stiffening of arterioles (21), or from glycemic damage or impaired autoregulatory function (22). It is thought to be distinct from macrovascular disease that refers to atherosclerosis, a disease of elastic and large muscular arteries characterized by atheroma formation. We found that microvascular and macrovascular abnormalities increased with advancing age and macrovascular abnormalities were more common in men. Although it is not clear whether one type of abnormalities leads to progression of the other type over time, worsening of white matter lesions by carotid artery stenosis-induced hypoperfusion (23) and the association between microvascular abnormalities and future macrovascular events among persons with diabetes (24) support for such progression. In our study, current smoking, low physical activity, hypertension, and diabetes were risk factors associated with predominantly microvascular abnormalities. They have been previously associated with microvascular disease in the brain (25–27), retina (28,29), and kidney (30,31). The prevalence of hypercholesterolemia was not increased in predominantly microvascular abnormalities, which is consistent with our understanding that cholesterol is a core element in the atherosclerotic lesions (21). We found higher prevalence of diabetes among those with predominantly macrovascular or both abnormalities. This is probably because most participants with diabetes may have already developed macrovascular abnormalities by the age when they entered our study. It has been reported that type 2 diabetes patients with microvascular complications are also likely to have severe macrovascular disease (32).

Our analysis offers insights into the prognostic implications of microvascular abnormalities in older adults. Despite lower prevalence of clinical CVD, individuals with high burden of microvascular abnormalities had shorter disability-free LEs than those with high burden of macrovascular abnormalities. Furthermore, a longer duration of severe disability in the presence of high burden of microvascular abnormalities alone or both abnormalities suggests the importance of microvascular abnormalities in maintaining independence in later life. Such difference could be attributed to executive dysfunction that was more strongly associated with microvascular abnormalities (3–5). Nonetheless, we found that many participants lived longer than 10 years, despite high burden of vascular abnormalities. This may reflect inherent adaptation to high vascular disease burden among surviving older adults who entered our study.

A unique strength of CHS is the assessment of an extensive list of microvascular and macrovascular abnormalities and key age-related outcomes in a large number of community-dwelling older adults. Our approach of estimating total and disability-free LEs accounts for the dynamic nature of disability and allows more intuitive interpretation. Because our definition of severe disability is directly related to quality of life and health care resource utilization, even a small difference in severe disability-free LE may be meaningful at both individual and population levels.

Our study has important limitations. In quantifying the vascular disease burden, different vascular abnormalities were weighted equally; loss of some information was inevitable when quantitative information was collapsed into categories. Some measures, such as electrocardiographic abnormalities or reduced glomerular filtration rate, may be manifestations of both microvascular and macrovascular abnormalities. In addition, there are no acceptable, clinically meaningful cut points to define high burden. To minimize the influence of cut points on our results, we compared LEs for 25th and 75th percentiles of each vascular index. Nonparticipation of sicker individuals in measurement of vascular abnormalities, selective survival into baseline of this analysis, and imputation of interval missing on disability (11–28% at each follow-up) by using the last nonmissing values (if participants did not respond due to worsening disability) might have underestimated the associations. Although the CHS participants were healthier than general population, the association of vascular abnormalities with functional status and LE in our study would not differ largely from general population.

Despite these limitations, our data suggest that microvascular and macrovascular abnormalities provide valuable prognostic information in community-dwelling older adults, including individuals without clinical CVD. Although having either or both microvascular and macrovascular abnormalities lowers the likelihood of longevity and functional independence, microvascular abnormalities may be more relevant for maintaining functional independence. It remains to be answered how to improve prognostication in older adults by optimally combining information from noninvasive tests with clinical history and functional assessment. Awaiting answers to these questions, clinicians should be alerted about the potential risk of reduced LEs and disability, when they see microvascular and macrovascular abnormalities on multiple noninvasive tests. Optimization of health status, advance care planning, and close monitoring of functional decline should be offered to individuals with high burden of microvascular or macrovascular abnormalities.

Funding

The work was supported by John A. Hartford Foundation Center of Excellence Award (to D.H.K., L.A.L.); the Charles A. King Trust Postdoctoral Fellowship Award from The Medical Foundation, a division of Health Resources in Action (to D.H.K.); the National Institutes of Health (P01-AG-004390, R37-AG-25037; to L.A.L.; R01-AG-023629, P30-AG-024827; to A.B.N.; R21-HL-077166;, contract NHLBI-HC-97-06; to R.K.; RO1-AG-027002; to M.J.S.; contracts HHSN268201200036C, HHSN268200800007C, N01HC55222, N01HC85079, N01HC85080, N01HC85081, N01HC85082, N01HC85083, N01HC85086;, and grant HL080295); the Research to Prevent Blindness Senior Scientific Award (to R.K.).

Supplementary Material

Acknowledgments

A full list of principal CHS investigators and institutions can be found at http://www.chs-nhlbi.org/PI.htm. L.A.L. holds the Irving and Edyth S. Usen and Family Chair in Geriatric Medicine at Hebrew SeniorLife. The funding sources did not have any role in the study design; collection, analysis, and interpretation of data; preparation of the manuscript; nor decision to submit it for publication.

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