Handgrip Strength and Cause-Specific and Total Mortality in Older Disabled Women: Exploring the Mechanism

Taina Rantanen, PhD,* Stefano Volpato, MD, MPH,* Luigi Ferrucci MD, PhD, Eino Heikkinen MD, PhD, Linda P. Fried, MD, MPH, and Jack M. Guralnik, MD, PhD*

OBJECTIVES: To examine the association between muscle strength and total and cause-specific mortality and the plausible contributing factors to this association, such as presence of diseases commonly underlying mortality, inflammation, nutritional deficiency, physical inactivity, smoking, and depression. DESIGN: Prospective population-based cohort study with mortality surveillance over 5 years. SETTING: Elderly women residing in the eastern half of Baltimore, Maryland, and part of Baltimore County. PARTICIPANTS: Nine hundred nineteen moderately to severely disabled women aged 65 to 101 who participated in handgrip strength testing at baseline as part of the Womens Health and Aging Study. MEASUREMENTS: Cardiovascular disease (CVD), cancer, respiratory disease, other measures (not CVD, respiratory, or cancer), total mortality, handgrip strength, and interleukin-6. RESULTS: Over the 5-year follow-up, 336 deaths occurred: 149 due to CVD, 59 due to cancer, 38 due to respiratory disease, and 90 due to other diseases. The unadjusted relative risk (RR) of CVD mortality was 3.21 (95% confidence interval (CI) 2.005.14) in the lowest and 1.88 (95% CI 1.113.21) in the middle compared with the highest tertile of handgrip strength. The unadjusted RR of respiratory mortality was 2.38 (95% CI 1.09 5.20) and other mortality 2.59 (95% CI 1.594.20) in the lowest versus the highest grip-strength tertile. Cancer mortality was not associated with grip strength. After adjusting for age, race, body height, and weight, the RR of CVD mortality decreased to 2.17 (95% CI 1.263.73) in the lowest and 1.56 (95% CI 0.892.71) in the middle, with the highest grip-strength tertile as the reference.

Further adjustments for multiple diseases, physical inactivity, smoking, interleukin-6, C-reactive protein, serum albumin, unintentional weight loss, and depressive symptoms did not materially change the risk estimates. Similar results were observed for all-cause mortality. CONCLUSION: In older disabled women, handgrip strength was a powerful predictor of cause-specific and total mortality. Presence of chronic diseases commonly underlying death or the mechanisms behind decline in muscle strength in chronic disease, such as inflammation, poor nutritional status, disuse, and depression, all of which are independent predictors of mortality, did not explain the association. Handgrip strength, an indicator of overall muscle strength, may predict mortality through mechanisms other than those leading from disease to muscle impairment. Grip strength tests may help identify patients at increased risk of deterioration of health. J Am Geriatr Soc 51:636641, 2003. Key words: handgrip strength; muscle strength; predictor of mortality; older disabled women

From the *Laboratory of Epidemiology, Demography and Biometry, National Institute on Aging, National Institutes of Health, Bethesda, Maryland; Department of Health Sciences, University of Jyvskyl, Jyvskyl, Finland; Geriatric Department, I Fraticini, National Research Institute, Florence, Italy; and Johns Hopkins Medical Institutions, Baltimore, Maryland. Address correspondence to Taina Rantanen, PhD, Department of Health Sciences, PO Box 35, Fin-40014, University of Jyvskyl, Finland. E-mail: Taina@maila.jyu.fi

andgrip strength, an easy test that correlates with elbow flexion strength (r 0.672), knee extension strength (r 0.514), and trunk extension strength (r 0.541) and thus gives an approximation of total body muscle strength,1 has been found to be a robust predictor of mortality and disability.2,3 The association between grip strength and mortality has been observed in multiple populations ranging from hospitalized female geriatric patients to healthy middle-aged men followed for 30 years, 36 but neither the association between strength and causespecific mortality nor the potential mechanisms explaining the association between muscle strength and mortality have been examined. Chronic conditions, such as coronary heart disease, stroke, chronic obstructive pulmonary disease (COPD), and diabetes mellitus are common underlying causes of death in old age. The presence of these diseases is associated with decreased muscle strength. 7 The suggested pathways from disease to muscle impairment include

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nutritional depletion, systemic inflammation, and physical inactivity;8 nutritional depletion, inflammation, and inactivity are also risk factors for mortality. 913 These findings suggest that poor muscle strength could be a marker of disease severity, which in turn is associated with mortality. Aging has been found to be associated with dysregulation of the inflammatory response, which may contribute to the pathophysiology of medical conditions and result in functional decline (for review, see14). During inflammation, interleukin-6 (IL-6) induces the synthesis of acutephase proteins in the liver, such as C-reactive protein (CRP), and inhibits the synthesis of albumin.15 It has been suggested that the low-grade catabolic effect of IL-6 may promote negative protein balance over time, eventually leading to sarcopenia, possibly accompanied by decline in strength.16 This is supported by observed correlation between high levels of CRP and IL-6 and low grip strength. 17 Furthermore, those having lower muscle mass, a primary determinant of strength, show lower levels of albumin. 18,19 Low levels of serum albumin are associated with cardiovascular disease (CVD) and all-cause mortality in older people and are suggested to be a marker of nutritional status and disease severity.9,10 Consequently, poor handgrip strength may be present in people who have low levels of albumin and high levels of CRP and IL-6 and who are thus at an increased risk of mortality. Depressed mood is another potential confounder of the association between handgrip strength and mortality. It is associated with increased risk of mortality20 and risk of accelerated decline in muscle strength.21 The aim of this study was to evaluate the association between handgrip strength and cardiovascular and allcause mortality in older disabled women over a period of 5 years and to explore the mechanism explaining the association between muscle strength and mortality. In addition to age, race, body size, smoking, and exercise, the potential mechanisms studied here comprised inflammation (indicated by CRP and IL-6), nutritional status (indicated by serum albumin and unintentional weight loss), depressed mood, and presence of chronic conditions. MATERIALS AND METHODS Participants The data used in these analyses were from the Womens Health and Aging Study, a prospective population-based study of the causes and course of disability in older women. The sampling and study eligibility criteria have been described in detail elsewhere.22 An age-stratified sample of 6,521 community-dwelling older women aged 65 and older residing in the eastern half of Baltimore and part of Baltimore county were identified from the Medicare eligibility files. Of these, 5,316 were living at home in the catchment area, 4,137 participated in the in-home screening, 1,409 met the criteria of study eligibility, and 1,002 (284 African Americans, 713 Caucasians, and 5 other) agreed to participate. The criteria were Mini-Mental State Examination23 score above 17 and self-reported difficulty in at least two of the following domains of physical function: upper extremity activities, mobility, basic self-care, and higher functioning tasks of daily living.

Handgrip Strength A trained nurse visited the participants in their homes and tested handgrip strength using a JAMAR hand dynamometer (Model BK-7498, Fred Sammons Inc., Brookfield, IL). Grip strength was measured in a seated position with the elbow flexed at 90. Grip strength was measured three times for each hand. During testing, the participant was strongly encouraged to exhibit the best possible force. The best measure in the stronger hand was used. Nine hundred nineteen women completed the handgrip strength test. The reasons for not completing the handgrip strength test were as follows: systolic blood pressure of 180 mmHg or greater or diastolic blood pressure of 110 mmHg or greater (n 55), pain (n 10), tester or participant felt test was unsafe (n 11), participant refused (n 2), and other (n 5). Biochemical Measures Blood samples were obtained from 720 participants. The nonrespondents were older (80.7 vs 77.4, P .001) and had lower grip strength (19.05 vs 20.9 kg, P .001) and lower body weight (65.3 vs 69.6 kg, P .001) than those who participated in the blood study. Presence of chronic conditions, race, and educational level did not differ between respondents and nonrespondents. For analytical purposes, each biochemical measure was recoded into five dichotomized variables: missing and lowest, second, third, and highest quartile. The cutoffs for quartiles were 3.80, 4.10, and 4.20 mg/dL for albumin; 2.00, 3.80, and 8.45 mg/dL for CRP; and 1.55, 2.40, and 3.67 pg/mL for IL-6. IL-6 was measured in duplicate using enzyme-linked immunosorbent assay from the frozen specimens with a commercial kit (High Sensitivity Quantikine kit, R & D Systems, Minneapolis, MN), and the average of the two measures was used in the analyses. CRP was measured using nephelometry from fresh serum, according to the method of Behring Diagnostic. Albumin was measured with dye-binding bromocresol green. Mortality Follow-Up Vital status was ascertained through follow-up interviews with proxies and from obituaries over the follow-up period. Over the 5 years, 336 deaths occurred. Death certificates were obtained for 318 subjects. The cause-specific mortality was based on underlying cause of death coded by one trained nosologist according to the International Classification of Diseases as any cardiovascular mortality (codes 390459, n 149), neoplasm mortality (codes 140239, n 59), respiratory mortality (codes 462519, n 38), or all other mortality (n 90). Other Measures Seventeen chronic diseases were ascertained at baseline with disease-specific standardized algorithms.24 The algorithms used data from the baseline interview, the nurses examination (including electrocardiogram, ankle-brachial index, and spirometry), and participants current medication list. Additional information was collected from medical records, blood test results, and a questionnaire sent to the participants primary care physicians. Diseases in the current analyses include congestive heart failure (CHF), stroke, COPD, diabetes mellitus, cancer, and hand osteoarthritis. The Geriatric Depression Scale (GDS) was

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Table 1. Characteristics of Participants According to Handgrip-Strength Tertiles

Grip-Strength Tertiles (N 919) Lowest (n 345) Characteristic Age Height, cm Weight, kg Walking, blocks/week Smoking, pack years Albumin, mg/dL C-reactive protein, mg/dL Interleukin-6, pg/mL Geriatric Depression Scale, points Chronic conditions, n 82.0 7.6 152.6 6.8 61.8 13.7 6.27 15.3 11.8 26.9 3.99 0.33 7.38 12.2 3.41 2.67 8.52 5.77 2.42 1.58 (345) (345) (345) (304) (340) (211) (198) (233) (345) (345) Middle (n 276) Mean Standard Deviation (n) 78.2 7.8 155.3 6.0 68.6 15.9 8.44 16.7 15.4 27.8 4.07 0.30 6.97 8.8 3.02 2.18 8.35 5.98 2.29 1.42 (276) (276) (276) (261) (272) (199) (187) (216) (276) (276) 73.8 6.4 159.1 6.3 76.7 15.9 10.4 19.6 18.3 31.8 4.06 0.29 6.31 5.62 2.93 2.41 6.86 5.0 2.22 1.43 (298) (298) (298) (277) (296) (230) (222) (243) (297) (298) Highest (n 298) One-Way ANOVA (P-value) .001 .001 .001 .001 .017 .054 .482 .079 .001 .242

ANOVA analysis of variance; SD standard deviation.

used to assess the participants emotional well-being, with higher scores indicating more depressive symptoms.25 Unintentional weight loss was determined based on responses to two questions: whether the participant had lost weight during the previous year and whether she had tried to lose weight, for example, through dieting or exercising. Smoking in pack years was calculated based on responses to questions on how many cigarettes per day and for how many years the participant smoked. Walking was queried as number of city blocks the participant walked per week. Statistical Methods Baseline characteristics were compared across tertiles of grip strength (18 kg, n 345; 18.122 kg, n 276, and 22 kg, n 298) using one-way analysis of variance or cross-tabulation with chi-square test. Death rates per 100 person-years were calculated. Survival between groups based on grip-strength tertiles was compared using Cox regression analyses. The variables hypothesized to explain the association between grip strength and mortality were progressively added in the model as covariates.

RESULTS At the baseline, the mean age was 78.3 (range 65101). Age and GDS score were inversely associated with grip strength, but body height and weight and number of city blocks walked per week were positively related with strength. IL-6 and CRP were somewhat but not significantly higher in those with poorer strength (Table 1). CHF and hand osteoarthritis were more common in those with poorer strength, whereas COPD and diabetes mellitus were more common in those with greater strength. Nutritional status was worse in those with poorer grip strength expressed as a greater proportion reporting unintentional weight loss (Table 2). Figure 1 shows the unadjusted rates for mortality according to grip-strength tertiles. There was a gradient of mortality rate for cardiovascular, respiratory, other (not CVD, not cancer, not respiratory), and total mortality, with the rate highest in the lowest tertile of grip strength. The unadjusted relative risk (RR) of CVD mortality was 3.21 (95% confidence interval (CI) 2.005.14) in the lowest and 1.88 (95% CI 1.113.21) in the middle ver-

Table 2. Participants with Chronic Condition and Those Reporting Unintentional Weight Loss According to Grip-Strength Tertiles
Grip-Strength Tertiles (N 919) Lowest (n 345) Condition Unintentional weight loss Congestive heart failure Stroke Chronic obstructive pulmonary disease Diabetes mellitus Cancer Hand osteoarthritis 29.3 14.2 6.7 15.1 11.6 14.5 27.0 Middle (n 276) % 20.3 9.8 5.4 13.8 17.4 20.3 21.0 14.4 6.7 8.4 23.2 19.8 11.1 18.5 Highest (n 298) Chi-Squared (P-value) .001 .008 .370 .005 .014 .008 .029

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Figure 1. Unadjusted rates of cause-specific and all-cause mortality according to grip-strength tertiles. Cause-specific mortality was based on underlying cause of death coded according to the International Classification of Diseases as any cardiovascular mortality (cardiovascular disease (CVD), codes 390459, n 149), neoplasm mortality (cancer, codes 140239, n 59), respiratory mortality (codes 462519, n 38), or all other mortality (n 96). P-values for trend: CVD, P .001; cancer P .829; respiratory, P .021; other, P .001; total, P .001.

tertile. Cancer mortality was not associated with grip strength. Mortality due to other diseases (not CVD, respiratory, or cancer) showed a risk gradient in the unadjusted analysis: 2.59 (95% CI 1.594.20) in the lowest and 1.21 (95% CI 0.682.19) in the middle compared with the highest third of grip strength. To explore the primary hypothesis of the mechanisms underlying the association between grip strength and mortality, covariates were introduced into the model relating grip strength to mortality (Table 3). This analysis was limited to CVD and total mortality, because the numbers in the other cause-of-death categories were not sufficient to perform a meaningful analysis. After adjusting the model for age, race, body weight, and height, the RR of CVD death decreased to 2.17 (95% CI 1.263.73) in the lowest and 1.56 (0.892.71) in the middle tertile of handgrip strength, with the highest tertile as the reference. Further adjustments for smoking, physical activity, diseases, nutritional status, or markers of inflammation did not materially change the result. For all-cause mortality, similar results were observed. Adding age, race, body weight, and height to the model decreased the RRs somewhat, but further adjustments did not change the results materially. DISCUSSION In older disabled women, handgrip strength was a powerful predictor of mortality due to CVD, respiratory diseases, and other diseases (not CVD, respiratory diseases, or cancer) and total mortality over a period of 5 years. Cancer mortality was not associated with baseline handgrip strength. The pathophysiological processes related to diseases commonly underlying death and associated with strength decline, such as inflammation, poor nutritional

sus the highest tertile of handgrip strength. Correspondingly, the unadjusted RRs for respiratory disease mortality were 2.39 (95% CI 1.095.20) in the lowest and 1.00 (0.372.71) in the middle versus the highest grip-strength

Table 3. Mortality According to Handgrip-Strength Tertiles, with the Highest Tertile as the Reference Group
Cardiovascular Disease Mortality Grip-Strength Tertiles Lowest vs Highest Covariate Unadjusted Characteristics Characteristics lifestyle Characteristics diseases Characteristics lifestyle diseases GDS Characteristics lifestyle diseases GDS Alb weight loss Characteristics lifestyle diseases GDS CRP Characteristics lifestyle diseases GDS IL-6 Characteristics life style diseases GDS Alb weight loss CRP IL-6 3.21 (2.005.14) 2.17 (1.263.73) 2.09 (1.153.78) 2.24 (1.293.91) 2.15 (1.173.93) 2.04 (1.113.75) 2.07 (1.133.81) 2.10 (1.143.88) 2.06 (1.113.83) Middle vs Highest All-Cause Mortality Grip-Strength Tertiles Lowest vs Highest Middle vs Highest

Relative Risk (95% Confidence Interval) 1.88 (1.113.21) 1.56 (0.892.71) 1.60 (0.882.89) 1.71 (0.973.01) 1.65 (0.903.04) 1.65 (0.903.04) 1.56 (0.842.88) 1.70 (0.923.13) 1.66 (0.903.07) 2.40 (1.793.22) 1.73 (1.232.43) 1.74 (1.202.50) 1.80 (1.272.56) 1.76 (1.212.57) 1.68 (1.152.44) 1.71 (1.172.50) 1.70 (1.162.48) 1.73 (1.202.48) 1.71 (1.242.37) 1.46 (1.042.05) 1.51 (1.052.17) 1.56 (1.102.21) 1.47 (1.052.09) 1.47 (1.012.13) 1.41 (0.962.04) 1.48 (1.022.15) 1.54 (1.082.20)

Characteristics age, weight, height, and race; diseases adjudicated congestive heart failure, stroke, chronic obstructive pulmonary disease, diabetes mellitus, cancer, and hand osteoarthritis at baseline; lifestyle smoking (pack years), walking (city blocks/week); GDS Geriatric Depression Scale; Alb serum albumin; weight loss self-reported unintentional loss of weight; CPR C-reactive protein; IL-6 interleukin-6.

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status, physical inactivity, and depression, did not explain the association between strength and mortality in the current study. To the best of the authors knowledge, this is the first population-based study examining the association between baseline handgrip strength and cause-specific mortality and the first attempt to capture the biological mechanism underlying this association. These results indicate that strength has a direct, nonspecific effect on mortality or is a marker of a third factor and that the effect is mediated through a mechanism not fully understood. Nevertheless, it is possible that selecting only disabled people in the study cohort may make it more difficult to capture the pathway explaining the greater mortality risk in those with poorer strength. Therefore, these analyses should be repeated in a population including healthier subjects and men, to positively exclude inflammation, nutritional depletion, depression, and physical inactivity as pathways explaining the association between strength and mortality. The direct effect of strength on mortality may be related to its role in the disablement process.2,26 In a previous analysis using data from the baseline of the current study, it was shown that poor strength was associated with reporting more difficulties in physical activities of daily living.26 Difficulties in performing daily activities correlated with cutting down the frequency of doing these activities. Low level of physical activity, in turn, predicted decline in muscle strength.6 Consequently, people with low muscle strength often are physically inactive and disabled, which makes them more vulnerable to accidents, such as injurious falls, or other adverse events. Inactive people are also at an increased risk of losing muscle mass.19 Muscle is the greatest reserve of protein in the body. In the case of trauma, negative amino acid balance occurs in muscle to help synthesize cellular components and antibodies in morecritical body systems. If the muscle has been depleted, healing may be compromised. Consequently, people with poor strength may be more prone to injurious accidents, and their recovery from acute diseases, injury, or surgery may be compromised.27 The health status of an older individual reflects lifelong exposure to a number of external stressors. Consequently, an accumulated biological burden present in body systems not addressed here (metabolic, neuro-endocrine) may be a mechanism explaining the association between strength and mortality and warrants further attention in future studies. The accumulation of dysfunction over years across major regulatory body systems, termed allostatic load, has been found to predict mortality and decline in physical functioning.28 A previous study, in which grip strength measured in midlife was found to track into later life and predict disability, supports the notion of earlierlife influences manifesting in later-life muscle strength and health status. This study of 8,006 men initially aged 45 to 68 and followed for 27 years, correlation between baseline and follow-up strength was r 0.557. This suggests that those who were strong in midlife remained strong into old age.7 In initially healthy middle-aged men, handgrip strength was also found to be a long-term predictor of disability and mortality.2,3 This raises the possibility that earlierlife influences on grip strength, such as early-life nutritional status or life-long physical activity, may have an effect on late-life mortality. Moreover, grip strength may be

a marker of resistance to external stressors. It is also worth noting that, in addition to muscle mass, neural drive from the motor cortex to muscles determines maximal voluntary muscle strength. Consequently, voluntary maximal handgrip strength may be a marker of efficacy of the central and peripheral nervous systems, motivation, or stamina, which may also affect survival. A limitation of the current study is that a measure of disease severity was not available. Thus, even though it cannot be excluded that grip strength predicts mortality because it indicated how sick the people were, it is unlikely that disease severity could entirely explain the association between strength and mortality. First, the association between strength and mortality risk has also been observed in a group containing only healthy people.3 Second, the models were adjusted for IL-6, serum albumin, unintentional weight loss, depressive symptoms, and physical inactivity. These variables may also be viewed as markers of severity of diseases.9,10,12 However, it is possible that grip strength could be an indicator of subclinical disease, which predicts mortality and is associated with lower muscle strength. It is unlikely that the selection of the study population could explain the association between handgrip strength and mortality. The cohort studied here represents the onethird most-disabled people living in the community. Consequently, the distribution of many variables, including grip strength, is truncated compared with that of a general population also including vigorous individuals. This would be expected to weaken, rather than strengthen, the association between grip strength and mortality. A selection process may have resulted in unexpected associations observed between crude disease prevalence and muscle strength. In the current study, diabetes mellitus and COPD were more common in those with greater grip strength, which is potentially explained by the positive association between grip strength and body weight and the lack of healthy, vigorous subjects in the study cohort. After adjusting for age, race, body height, weight, and smoking, the association between higher strength and presence of COPD and diabetes mellitus disappeared. Handgrip strength, an easy measure of muscle strength, was a powerful predictor of CVD, respiratory, and total mortality over a period of 5 years. This association was mediated through mechanisms other than presence of diseases commonly underlying death, inflammation, nutritional depletion, depression, inactivity, or smoking. A grip-strength test may be a simple measure to help identify patients at an increased risk of deterioration of health. REFERENCES
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