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a The University of Pittsburgh, Pennsylvania
b St. Francis Hospital, Roslyn, New York
c The University of Washington, Seattle
d The University of California at Davis, Sacramento
e Georgetown University Medical Center, Washington, DC, and Uniformed Services University of the Health Sciences, Bethesda, Maryland
f The University of Vermont, Colchester
g Johns Hopkins University, Baltimore
Anne B. Newman, Division of Geriatric Medicine, University of Pittsburgh School of Medicine, 3520 Fifth Avenue, Suite 300, Pittsburgh, PA 15090 E-mail: anewman+{at}pitt.edu.
Decision Editor: John E. Morley, MB, Bch
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Abstract |
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Methods. Frailty status was defined in participants of the Cardiovascular Health Study (CHS), a cohort of 5,201 community-dwelling older adults, based on the presence of three out of five clinical criteria. The five criteria included self-reported weight loss, low grip strength, low energy, slow gait speed, and low physical activity. We examined the spectrum of clinical and subclinical cardiovascular disease in those who were frail (3/5 criteria) or of intermediate frailty status (1or 2/5 criteria), compared to those who were not frail (0/5). We hypothesized that the severity of frailty would be related to a higher prevalence of reported cardiovascular disease (CVD), as well as to a greater extent of CVD, measured by noninvasive testing.
Results. Of 4,735 eligible participants, 2,289 (48%) were not frail, 299 (6%) were frail, and 2,147 (45%) were of intermediate frailty status. Those who were frail were older (77.2 yrs) compared to those who were not frail (71.5 yrs) or intermediate (73.4 yrs) (p < .001). Frailty status was associated with clinical CVD and most strongly with congestive heart failure (odds ratio [OR] = 7.51 (95% confidence interval [CI] = 4.66–12.12). In those without a history of a CVD event (n = 1,259), frailty was associated with many noninvasive measures of CVD. Those with carotid stenosis >75% (adjusted OR = 3.41), ankle-arm index <0.8 (adjusted OR = 3.17) or 0.8–0.9 (adjusted OR = 2.01), major electrocardiography (ECG) abnormalities (adjusted OR = 1.58), greater left ventricular (LV) mass by echocardiography (adjusted OR = 1.16), and higher degree of infarct-like lesions in the brain (adjusted OR = 1.71), were more likely to be frail compared to those who were not frail. The overall associations of each of these noninvasive measures of CVD with frailty level were significant (all p < .05).
Conclusions. Cardiovascular disease was associated with an increased likelihood of frail health. In those with no history of CVD, the extent of underlying cardiovascular disease measured by carotid ultrasound and ankle–arm index, LV hypertrophy by ECG and echocardiography, was related to frailty. Infarct-like lesions in the brain on magnet resonance imaging were related to frailty as well.
FRAIL older adults are a group at high risk for morbidity and mortality (1). Many studies have equated frailty with disability or multiple comorbidities (2)(3)(4). Fried and Walston (5) have proposed that frailty is a distinct clinical syndrome related to poorly understood underlying physiologic changes associated with aging that result in decreased strength, speed, and activity, weight loss and low energy, and as such is distinct from disability. Using data from the Cardiovascular Health Study (CHS), we developed a standardized definition for the clinical syndrome of frailty that does not depend on the presence of disability or comorbidity. Based on a consensus of clinicians, frailty was defined as a clinical syndrome or a constellation of signs and symptoms in which at least three of five possible criteria are present: (i) low strength, (ii) slow walking speed, (iii) low physical activity, (iv) self-reported unintentional weight loss, and (v) self-reported exhaustion. Thus, in this conceptualization of frailty, disease may be present either overtly or subclinically; it could play an etiologic role, although the presence of clinically apparent disease is not a necessary component of the frailty syndrome. Validation work has shown that those meeting this definition of frailty were more likely to die, be hospitalized, or become disabled over 6 years of follow-up, independent of age and other risk factors for mortality (6).
The CHS was established to evaluate cardiovascular disease (CVD) and its risk factors in older adults. At the inception of the CHS, approximately a third of the 5,201 initially enrolled subjects had clinical CVD and another third had evidence of subclinical CVD on noninvasive testing with carotid ultrasound, echocardiography, or other tests (7). Conversely, about one third of the CHS participants had neither clinical nor subclinical CVD. The extent of subclinical disease has been shown to be a strong predictor of future clinical CVD (8)(9)(10). In this study, we sought to characterize the relationship of the underlying extent of subclinical and clinical CVD to level of frailty, in those who were defined as frail or intermediate, compared to the nonfrail. We hypothesized that, even in those without clinically manifest CVD, the extent of underlying abnormalities in cardiovascular structure and function would be independently related to frailty status.
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Methods |
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Clinical Exam
All participants underwent a baseline medical history and examination focused on CVD, including systolic (SBP) and diastolic blood pressure (DBP), ECG, ankle–arm index, carotid ultrasound, echocardiography, and pulmonary function testing (11). At the baseline exam, participants were classified according to the presence or absence of six preexisting cardiovascular diagnoses: myocardial infarction (MI), angina, congestive heart failure (CHF), transient ischemic attack (TIA), stroke, and intermittent claudication. Those with any of these six conditions were classified as having prevalent CVD. The methods of ascertainment of these conditions have been described elsewhere (12)(13)(14)(15).
Definition of Frailty
We have defined the syndrome of frailty as a constellation of five specific signs and symptoms, of which at least three must be present. Those with none of these criteria were considered to be nonfrail, and those with one or two criteria were considered to be an intermediate group. Conceptually, the syndrome includes domains of "shrinking," weakness, lack of energy, slowness, and sedentariness (5). Using data available in CHS, the definition was simplified and standardized as follows:
Noninvasive Assessment of Cardiovascular Disease
Carotid ultrasound.--
To quantify the degree of thickening of the carotid artery walls, bilateral measures of intimal–medial thickening (IMT) were summarized into two variables, one for the left and right internal carotid artery and one for the left and right common carotid artery, using B-Mode Ultrasound. Plaque was described, according percent maximal stenosis for each internal carotid artery (13).
Ankle–arm index.--
The ankle–arm index (AAI) was performed to assess the degree of lower extremity arterial disease. The AAI is the ratio of the ankle to arm systolic blood pressure and is reduced to less than 0.9 when there is obstruction to blood flow in the leg (19). For these analyses, progressive decrements in the AAI < 1.0 were categorized in 0.1 decrements: >1.0, >0.9–
1.0, 
0.8–0.9, <0.8.
Electrocardiography.-- ECG abnormalities were determined by the CHS ECG Reading Center according to a standard protocol (20). Major ECG abnormalities included ventricular conduction defects, major Q or QS abnormalities, minor Q or QS with ST-T-wave abnormalities, left ventricular (LV) hypertrophy, isolated major ST-T-wave changes, atrial fibrillation or first degree atrioventricular block (21).
Echocardiography.--
Several quantitative parameters describing cardiac size, and systolic and diastolic function were examined, including the dimensions of the LV cavity, posterior and septal walls, and left atrium, velocities in early (Epk) and late (Apk) diastole, and LV mass (22)(23). LV fractional shortening, a quantitative measure of LV systolic function, LV combined wall thickness, and circumferential LV end-systolic wall stress were calculated as described elsewhere (24). The qualitative global LV function was categorized by visual assessment as "normal" (corresponding to an ejection fraction (EF) of 55%), as "borderline" (corresponding to EF of 45–54%), or as "abnormal" (corresponding to an EF of <45%). Regional wall motion abnormalities were assigned coding of "normal," "mildly abnormal," "moderately abnormal," or "severely abnormal" (25)(26).
Cerebral magnetic resonance imaging.-- Cerebral magnetic resonance imaging (MRI) was performed in 1992–93 (27). White matter disease was estimated in comparison to eight standard studies that successively increased from no changes (grade 0) to extensive confluent changes (grade 9). Infarct-like lesions (ILL) were defined as present when >3mm (22)(28). The sulcal prominence and ventricular size in each individual were assessed on a semiquantitative 10-point scale (grades of 0–9) (27).
Statistical Analysis
Descriptive analyses included inspection of frequencies, histograms, and error bar plots to examine bivariate relationships of clinical and subclinical measures of CVD with frailty level. For bivariate associations, Pearson chi-square tests were used to evaluate associations between categorical variables, analysis of variance (ANOVA) F-tests for associations between continuous and categorical variables.
Because frailty was defined as a three-level categorical outcome variable, multinomial logistic regression was performed to evaluate relationships between frailty level and CVD measures. Odds ratios (ORs) were estimated for the intermediate and frail groups with respect to the nonfrail group. P values reported correspond to the null hypothesis that the ORs of interest for both groups are simultaneously equal to zero, the alternative hypothesis being that at least one OR is statistically significantly different from zero. Univariate 95% confidence intervals (CIs) are also presented for each estimate. All regressions were adjusted for age, gender, and race. Regressions involving echocardiographic measures were also adjusted for weight, height, and systolic blood pressure. Continuous variables were assessed for the linearity of their relationship with the logit function by examining the categorical codings of the variables in the regression models. Categories were determined based upon quintiles for the frail group, resulting in sufficient numbers at each frailty level to provide relatively stable OR estimates for each category. When nonlinear relationships were detected, the model was fit with piecewise linear terms. Break points for the piecewise terms (29) were determined by fitting a logistic regression (combining the frail and intermediate groups) with the adjustment covariates only. The residuals were then plotted versus the variable of interest using a scatterplot smoothing function in S-Plus and the break points chosen based on visual inspection of the plot. For these models, an additional degree of freedom was assessed in the hypothesis tests to account for the "estimation" of this additional parameter. However, due to the large number of statistical tests performed, in general, p values should not be strictly interpreted but are presented to illustrate the relative strength of association between frailty level and measures of CVD. Analyses were carried out using the SPSS for Windows, STATA (StatCorp), and S-Plus for Windows (S-PLUS) statistical packages.
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Results |
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3 characteristics were characterized as frail, 2,147 (45.3%) as intermediate status (1 or 2 characteristics), and the remaining 2,289 (48.3%) as not frail (Table 1 ). Those deemed frail were older (mean age of 77.2 years vs 73.4 in the intermediate group vs 71.5 in the nonfrail group). A higher proportion of frail elders were women or African American. Those who were frail had less education and lower income. Education and income were strongly associated with race. All subsequent analyses were adjusted for age, gender, and race.
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125 mm Hg. For those with SBP <125 mmHg, increase in SBP of 10 mm Hg was associated with about a 25% decrease in the odds of being frail. For SBP 125, further increases in BP were associated with an increased odds of being frail of about 15% per 10mm Hg. SBP was not associated with intermediate frailty status. Diastolic blood pressure was also associated with frailty (p = .003), though the range was small. Pulse pressure was not associated with frailty.
Carotid Disease
Those who were frail, as well as those who were intermediate, were more likely to have higher levels of carotid stenosis. Of the nonfrail group, 0.3% had >75% stenosis; 0.7% of the intermediate group and 1.6% of the frail group also had >75% stenosis (Table 4 ). At higher levels of stenosis (>75%), the sample size, especially in the frail group, was quite small, thus the confidence intervals around the OR became quite wide (Table 5 ). Nevertheless, the overall p value in this model is consistent with increasing likelihood of frailty with increasing level of stenosis. Carotid wall thicknesses were also strongly related to frailty level. Mean internal carotid IMT increased from 1.31 mm in the nonfrail to 1.42 mm in the intermediate group and 1.51 mm in the frail group. Similarly higher values for mean common carotid wall thickness were noted (Table 5 ). Fig. 1 shows the age-, race-, and gender-adjusted mean maximal internal carotid wall thickness in those with and without clinical CVD and overall. The trend of increasing wall thickness with greater frailty status was more apparent in the absence of clinical CVD.
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0.9 (Table 5 ).
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140 gm. For those with LVM 140, further increases in LVM were associated with increased odds of being intermediate or frail compared to the nonfrail group. The OR for a 25 gm increase in LVM was 1.10 (95% CI = 1.04, 1.17) for intermediate versus nonfrail and was 1.16 (95% CI = 1.03, 1.31) for the frail versus the nonfrail group.
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Cerebral MRI
Several measures of vascular disease in the brain were evaluated with respect to frailty and are shown in those without clinical CVD at baseline in Table 4 and Table 5 . Most striking was the association of the presence of infarct-like lesions with frailty, increasing from 22.3% in the nonfrail to 29.5% in the intermediate and 37.1% in the frail group (Table 4 ), overall p = .005 (Table 5 ). This relationship was similar in those with and without clinical CVD (Fig. 5).
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CVD and Frailty: Racial Comparisons
In order to determine whether these findings were consistent across race, comparisons were made for three measures of the extent of atherosclerosis common to both cohorts that included the additional 687 African Americans. As shown previously in the CHS, both frailty and CVD were more prevalent in African Americans. Frailty status was significantly associated with lower AAI and a higher prevalence of infarct-like lesions on brain MRI in both Caucasians and African Americans (all p < .05). Common carotid wall thickness was associated with frailty status in Caucasians. A similar but nonsignificant trend was noted in the African American cohort.
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Discussion |
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The finding of an association between clinical CVD and frailty was expected, whereas the findings of broad associations with subclinical disease markers and frailty were less predictable. We expected that excluding those with clinical disease might well have excluded those with the most extensive underlying abnormalities on noninvasive testing. In these analyses, excluding those with clinical disease attenuated some of these relationships to a degree, but did not negate them.
We hypothesize that these relationships between frailty and CVD may be explained by two different, but not mutually exclusive, pathways. The first explanation might be that the noninvasive measures of disease represent subclinical end organ damage, thus decreasing total physiologic reserve. The second possibility is that atherosclerosis, as a state of chronic inflammation, may result in a catabolic state with its systemic manifestations contributing to frailty.
It has been established that those with greater abnormalities in the arterial tree are likely to have a higher prevalence of end organ damage, particularly in the heart, brain, and kidneys. For example, CHS participants with lower extremity arterial disease are more likely to have wall motion abnormalities on echocardiography and a higher serum creatinine (30), and those with higher carotid wall thickness are more likely to have infarct-like lesions on cerebral MRI (31). It is possible that impairment in these important organs explains the association of these abnormalities of arterial structure and function with the clinical phenotype of frailty (5). There may be reduced physiologic functional reserve in these organs that is not sufficient to have caused a clinical event (such as myocardial infarction or stroke), but is sufficient to cause a reduction in the ability to respond to environmental challenges, such as exercise, emotional distress, or infection. This subclinical reduction in end organ reserve is hypothesized to be part of the underlying pathophysiology that is recognized clinically as frailty (6). Since atherosclerosis is a systemic disease, these individuals may have accumulated subclinical end organ damage in multiple vascular beds. Our data support this hypothesis, in that some of our measures that capture end organ damage, such as infarct-like lesions by MRI and major ECG abnormalities (including both ischemic changes and left ventricular hypertrophy), were associated with frailty status.
Previous work in CHS as well as in other cardiovascular cohort studies (19)(32)(33) has illustrated that there is a substantial burden of subclinical atherosclerosis in older adults. Atherosclerosis has been increasingly viewed as a disease of chronic inflammation (34), with data linking inflammation to the development of early lesions (35) as well as with the active process of thrombosis associated with plaque rupture (36). Studies of aging have shown that markers of chronic inflammation, such as low albumin and increased interleukin-6, are increased with age (37) and associated with incident disability (38)(39) as well as cardiovascular (40) and total mortality (41). A person with a large degree of plaque who continues to escape a major cardiovascular event has had numerous inflammatory and thrombotic events in the vessel wall. This process may explain the association of higher levels of C-reactive protein (42)(43)(44) and fibrinogen with incident CVD (45)(46). Thus, the ongoing healing, remodeling, and calcification associated with the accumulation of atherosclerotic plaque with age, through episodic or chronic inflammation, could contribute to the loss of lean mass and decreased appetite characteristic of chronic inflammatory states (47) and of frailty (5). Thus, the cost of surviving acute cardiovascular events may be that a chronic inflammatory state is maintained to continue to heal these extensive lesions, with resulting loss of strength, weight loss, inactivity, and poor appetite. The data support this hypothesis in that the degree of frailty is related to the extent of atherosclerosis in all vascular beds examined.
Frailty appeared to be associated with reduced global LV function as well as increased LV mass (by ECG as well as by echocardiography), suggesting that those who are frail have relatively poorer functioning myocardium or an increase in the proportion of LV mass that is noncontractile tissue. Several of the other echocardiographic parameters associated with frailty support the idea that frailty may be associated with diastolic failure and vascular stiffness. These include the relationship of frailty with increased late peak flow and greater LV wall thickness, as well as a nonlinear or "j-shaped" relationship with systolic blood pressure. The association of frailty with clinical CHF supports the possibility that those who are frail have increased levels of inflammation, such as circulating tumor necrosis factor (48), leading to myocardial dysfunction. Future studies of frailty should directly assess markers of inflammation such as tumor necrosis factor or interleukin-6 as mediators of these relationships.
The associations of frailty status with white matter grade and infarct-like lesion on MRI also support another hypothesis of substantial clinical relevance, that those who are frail may be at risk for cognitive impairment as well. We did not include cognitive impairment in our conceptualization of frailty and excluded those who were demented at baseline from these analyses. Nevertheless, these unique data support the clinician's view that those who are frail are cognitively fragile and may be at risk for delirium and dementia (5).
Several important limitations must be considered in examining these data. First, our definition of frailty was assessed using measures obtained at the baseline examination. Weight loss, for example, was assessed by self-report, and measures of low energy were taken from the CES–D inventory. Future work should include measured weight changes, including changes in lean mass. A more detailed measure of fatigue or lack of energy may also improve the definition of frailty. Nevertheless, in related analyses, the criteria developed appear to be valid in that those meeting these criteria for frailty were more likely to die or become disabled, even when adjusting for known risk factors (6). Finally, the current associations are cross-sectional, and are not necessarily causal.
In summary, these findings suggest that the extent of atherosclerosis may be a precipitant of frailty in older adults. Alternatively or additionally, these noninvasive measures of CVD may reflect cumulative, subclinical end organ damage with decreased physiologic reserve that is systemically manifest as frailty. Further definition of these relationships could lead to substantially greater understanding of the consequences of cardiovascular disease in older adults as well as a basis for understanding the part of physical frailty that results from CVD.
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Acknowledgments |
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*The opinions and asssertions expressed herein are those of the authors and should not be construed as reflecting those of the Uniformed Services University of the Health Sciences or the U.S. Department of Defense.
Participating Institutions and Principal Staff: Forsyth County, NC—Bowman Gray School of Medicine of Wake Forest University: Gregory L. Burke, Sharon Jackson, Alan Elster, Curt D. Furberg, Gerardo Heiss, Dalane Kitzman, Margie Lamb, David S. Lefkowitz, Mary F. Lyles, Cathy Nunn, Ward Riley, John Chen, Beverly Tucker; Forsyth County, NC—Wake Forest University–ECG Reading Center: Farida Rautaharju, Pentti Rautaharju; Sacramento County, CA—University of California, Davis: William Bonekat, Charles Bernick, Michael Buonocore, Mary Haan, Calvin Hirsch, Lawrence Laslett, Marshall Lee, John Robbins, William Seavey, Richard White; Washington County, MD—The Johns Hopkins University: M. Jan Busby-Whitehead, Joyce Chabot, George W. Comstock, Adrian Dobs, Linda P. Fried, Joel G. Hill, Steven J. Kittner, Shiriki Kumanyika, David Levine, Joao A. Lima, Neil R. Powe, Thomas R. Price, Jeff Williamson, Moyses Szklo, Melvyn Tockman; MRI Reading Center—Washington County, MD—The Johns Hopkins University: Norman Beauchamp, R. Nick Bryan, Douglas Fellows, Melanie Hawkins, Patrice Holtz, Naiyer Iman, Michael Kraut, Cynthia Quinn, Grace Lee, Carolyn C. Meltzer, Larry Schertz, Earl P. Steinberg, Scott Wells, Linda Wilkins, Nancy C. Yue; Allegheny County, PA—University of Pittsburgh: Diane G. Ives, Charles A. Jungreis, Laurie Knepper, Lewis H. Kuller, Elaine Meilahn, Peg Meyer, Roberta Moyer, Anne Newman, Richard Schulz, Vivienne E. Smith, Sidney K. Wolfson; Echocardiography Reading Center (Baseline)—University of California, Irvine: Hoda Anton-Culver, Julius M. Gardin, Margaret Knoll, Tom Kurosaki, Nathan Wong; Echocardiography Reading Center (Follow-up)—Georgetown Medical Center: John Gottdiener, Eva Hausner, Stephen Kraus, Judy Gay, Sue Livengood, Mary Ann Yohe, Retha Webb; Ultrasound Reading Center—New England Medical Center, Boston: Daniel H. O'Leary, Joseph F. Polak, Laurie Funk; Central Blood Analysis Laboratory—University of Vermont: Elaine Cornell, Mary Cushman, Russell P. Tracy; Pulmonary Reading Center—University of Arizona–Tucson: Paul Enright; Coordinating Center—University of Washington, Seattle: Alice Arnold, Annette L. Fitzpatrick, Richard A. Kronmal, Bruce M. Psaty, David S. Siscovick, Will Longstreth, Patricia W. Wahl, David Yanez, Paula Diehr, Corrine Dulberg, Bonnie Lind, Thomas Lumley, Ellen O'Meara, Jennifer Nelson, Charles Spiekerman; NHLBI Project Office: Robin Boineau, Teri A. Manolio, Peter J. Savage, Patricia Smith.
Received June 21, 2000
Accepted July 5, 2000
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