AS179 - Frailty in WHI: drugs, inflammatory and genetic markers

Investigator Names and Contact Information

Andrea LaCroix (alacroix@ucsd.edu)

Introduction/Intent

Disability, as measured in terms of chronic limitations or dependency in mobility, activities of daily living (ADLs) or instrument activities of daily living (IADLs), is a common public health problem in older adults. “Frailty” which is distinct from disability, is a term that has been used clinically to describe a constellation of changes that occur in the very old such as impaired strength, endurance and balance. Prevalence of frailty in the Cardiovascular Health Study was estimated to be 7.3% in women and 4.9% in men aged 65 and older. In minority women, the prevalence of frailty was 14.4%. Thus, women suffer disproportionately from this vulnerable state.

Understanding the biological mechanisms for frailty and disability would allow the development and testing of preventive interventions. Evidence exists that markers of chronic inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), fibrinogen) and coagulation (D-dimer) increase the risk for incident disability. However data examining the role of mediators of chronic inflammation and coagulation in developing frailty is scant. We postulate that statins and angiotensin converting enzyme (ACE) inhibitors are two classes of medications that may prevent frailty and disability via their effects on mediators of chronic inflammation and/or coagulation, however, little research has been done in this area. We further postulate that markers of inflammation and coagulation are associated with increased risk of frailty in older women in the absence of an intervening acute health event (cardiovascular disease or cancer). Finally, we postulate that older women with the specific genotypes described below have a different risk of frailty or disability than women without such genotypes. A nested case-control study in the WHI Observational Study is proposed to test these hypotheses.

Specific aims

1. To examine whether use of statins and/or ACE inhibitors is associated with lower risk for developing the syndrome of frailty or disability.

2. To determine if markers of chronic inflammation (CRP, interleukin-6 (IL-6)), fibrinogen, Factor VII, Factor VIII) and/or coagulation pathways (PAP complex, D-dimer, Factor XI a1-antitrypsin) are associated with the syndrome of frailty or disability (in those without MI, stroke, cancer or diabetes).

3. To determine if the ACE gene insertion (I) polymorphism or one of two promoter polymorphisms (-174G/C and -572G/C ) of the IL-6 gene is associated with risk for developing the syndrome of frailty or disability.

4. If a protective association is found between statin or ACE inhibitor use and the development of frailty or disability:

   4.a. To investigate if any protective effects of these medications are mediated through markers of chronic inflammation and/or coagulation pathways.

   4.b. To investigate whether any protective associations are modified by ACE gene insertion (I) polymorphism or one of two promoter polymorphisms (-174G/C and -572G/C ) of the IL-6 gene.

Results/Findings

Some of the publications related to this ancillary study are:

Ms301 - Gray SL, LaCroix AZ, Aragaki AK, McDermott M, Cochrane BB, Kooperberg CL, Murray AM, Rodriguez B, Black H, Woods NF; Women's Health Initiative Observational Study. Angiotensin-converting enzyme inhibitor use and incident frailty in women aged 65 and older: prospective findings from the Women's Health Initiative Observational Study. J Am Geriatr Soc. 2009 Feb;57(2):297-303.

Ms302 - Woods NF, LaCroix AZ, Gray SL, Aragaki A, Cochrane BB, Brunner RL, Masaki K, Murray A, Newman AB. Frailty: Emergence and consequences in women aged 65 and older in the Women's Health Initiative Observational Study. J Am Geriatr Soc. 2005 Aug;53(8):1321-30.

Ms303 - Lacroix AZ, Gray SL, Aragaki A, Cochrane BB, Newman AB, Kooperberg CL, Black H, Curb JD, Greenland P, Woods NF. Statin use and incident frailty in women aged 65 years or older: Prospective findings from the Women's Health Initiative Observational Study. J Gerontol A Biol Sci Med Sci. 2008 Apr;63(4):369-75.

Ms662 - Reiner AP, Aragaki AK, Gray SL, Wactawski-Wende J, Cauley JA, Cochrane BB, Kooperberg CL, Woods NF, Lacroix AZ. Inflammation and Thrombosis Biomarkers and Incident Frailty in Postmenopausal Women. Am J Med. 2009 Oct;122(10):947-54. Epub 2009 Aug 13

Ms831 - Beasley JM, LaCroix AZ, Neuhouser ML, Huang Y, Tinker L, Woods N, Michael Y, Curb JD, and Prentice RL. Protein intake and incident frailty in the Women’s Health Initiative Observational Study. J Am Geriatr Soc. 2010 May 7 [Epub ahead of print]

For a complete, up-to-date list of WHI papers related to this ancillary study, please use the searchable Bibliography section of this website. To search for papers by study number, access the Simple Search, and enter the study number in the “Related Studies” field.