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• W2941943265 abstract "HomeCirculationVol. 139, No. 17Putting the Measurement of Physical Capacity of Older Adults in Its Place Free AccessEditorialPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessEditorialPDF/EPUBPutting the Measurement of Physical Capacity of Older Adults in Its Place Stephen B. Kritchevsky, PhD Stephen B. KritchevskyStephen B. Kritchevsky Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC. Search for more papers by this author Originally published23 Apr 2019https://doi.org/10.1161/CIRCULATIONAHA.119.039116Circulation. 2019;139:2000–2002This article is a commentary on the followingSystemic Inflammation and Cardio-Renal Organ Damage Biomarkers in Middle Age Are Associated With Physical Capability Up to 9 Years LaterArticle, see p 1988The article by Kuh and colleagues1 appearing in this issue of Circulation relates biomarkers of cardiovascular disease risk and end-organ damage to declines in physical capacity in 1736 British 60- to 64-year-olds. This article is notable for 2 reasons. The dependent variables it considers are related to physical function, not cardiovascular function; and it provides the opportunity to place cardiovascular disease in the context of an emerging geroscience paradigm which holds that the occurrence of age-associated diseases including cardiovascular disease is attributable, in part, to fundamental aging biology. Its overarching hypothesis is that age-related disease can be delayed by intervening in aging biology, a strategy that is distinct from the current approach, which focuses on specific pathways to prevent specific diseases.The study participants were drawn from a cohort of men and women born in 1946 in England, Scotland, and Wales. When the cohort reached 69 years of age, examiners measured 4 aspects of physical performance: grip strength, chair rise speed, normal-paced walking speed, and 1-legged standing balance time. Similar measures had been collected up to 9 years earlier when the participants were 60 to 64 years old. Using blood from the earlier visit, the investigators measured NT-proBNP (N-terminal pro-B-type natriuretic peptide), cystatin C, E-selectin, and interleukin 6 (IL-6) to represent end-organ distress and inflammation. They related marker levels to physical performance at follow-up in a series of nested regression models adjusting first for sex, then adding height and body mass index, then physical performance levels at baseline, and finally the presence of diabetes mellitus, cardiovascular disease or kidney disease, other cardiovascular risk factors, and a measure of lifetime socioeconomic position.With 4 biomarkers and 4 outcomes and 4 different statistical models, there are a lot of results to sort through. Adjusting for only sex, height, and body mass index, all 4 markers were associated with all 4 physical measures. Research shows that poorer performance in each functional domain measured by Kuh et al1 predicts mortality and disability, but that gait speed tends to be most informative.2 In the analysis by Kuh et al, once baseline performance was taken into account, cystatin C, NT-proBNP, and IL-6 levels continued to be independently related to grip strength and walking speed, with NT-proBNP and IL-6 showing the strongest associations. Finally, after adjusting for other cardiovascular disease risk factors and prevalent cardiovascular disease, diabetes mellitus, and kidney disease, NT-proBNP and IL-6 levels remained associated with strength and walking speed, but the association with cystatin C was attenuated. There is a caveat with respect to cystatin C. The classification of kidney disease at baseline was based on cystatin C levels, so adjusting for kidney disease may have resulted in overadjustment unfairly diminishing the strength of the association with cystatin C. Nevertheless, measures of end-organ distress and inflammation are clearly associated with faster declines in physical performance in adults in their early 60s, even accounting for prevalent clinically manifest cardiorenal disease and standard cardiovascular disease risk factors. Although there have been similar previous reports for IL-6 and cystatin C, this is the first study to link NT-proBNP to physical function in such a way. The BIOSTAT-CHF study (Systems Biology Study to Tailored Treatment in Chronic Heart Failure) recently reported that baseline NT-proBNP levels were associated with 6-minute walk distance in heart failure patients, who differ markedly from the community-dwelling population considered here.3 The median levels measured by Kuh et al were quite low (55 pg/mL) and many-fold lower than those seen in heart failure, and the relationship with function was linear across the observed range, suggesting that this measure is not a proxy for undiagnosed heart failure.Grip strength, walking speed, balance, and the ability to rise from a chair are measures of physical capacity. The term physical capacity deserves some elaboration. Nagi4 proposed a model to help study the trajectories of functional decline. In this model, disease pathology “impairs” organ function. Sufficient impairment leads to “limitation” reflected in difficulty in performing activities. Severe limitations can result in “disability” or the inability to perform tasks independently. The World Health Organization proposed an expanded model which denominates “body structures and functions” that support the performance of “activities” which, in turn, permit “participation” in and fulfillment of social roles (as a less pejorative framing than “disability”).5Why should cardiovascular disease researchers be concerned with physical capacity? Quoting a 2017 American Heart Association scientific statement, “Adults are living longer, and cardiovascular disease is endemic in the growing population of older adults who are surviving into old age. Functional capacity is a key metric in this population, both for the perspective it provides on aggregate health and as a vital goal of care.”6 This deserves amplification. Research across a variety of medical subspecialties has shown that measures of physical function predict care outcomes beyond measures related to a specific organ or organ system.7 The interpretation of disease risk factors can differ by functional status as can the odds of treatment success. Gait speed, in particular, predicts mortality and complications in patients with various kinds of heart disease beyond ejection fraction or other cardiovascular specific metrics. Furthermore, physical and cognitive functional capacity are at the core of living independently, which many older patients value above life itself.8 Thus, anyone treating an older patient should be prepared to discuss prospective treatments with respect to their likelihood of risk and benefits to functional capacity.Walking and other physical functions are not the domain of any single subspecialty. Walking speed not only reflects the cardiovascular system but also is affected by mood, anemia, lower extremity pain, strength, obesity, and peripheral neuropathy.7 Maneuvers that restore the function of a single organ may not improve physical capacity. In 1 series, 28% of patients undergoing transcatheter aortic valve replacement realize no functional benefit from the procedure as reflected by 6-minute walk time.9 Perhaps having a fuller understanding of how all the contributors to functional capacity interact could help better predict whether a given older patient’s function is likely to benefit from a procedure targeting the heart.After midlife, physical capacity declines, a process that accelerates late in life. This observation is not unique to humans. The loss of speed is a hallmark of aging in virtually all mammalian species. Until relatively recently, most believed that aging was immutable. Advances in the biology of aging have shown this not to be true; lifespan can be extended by genetic manipulation, by restricting energy intake, or by pharmacological means in multiple animal models.10 As animals live longer, the onset of chronic diseases is also delayed, and in the case of caloric restriction, physical function is also maintained. This observation has inspired a new field, geroscience, which seeks to improve human health through targeting the biology of aging. The hope is that by targeting aging biology, one can simultaneously slow multiple age-related diseases, including cancer, cardiovascular disease, and Alzheimer disease. This is distinct from the current model of preventing disease, which is based on identifying specific pathways to specific diseases and developing interventions targeting these pathways. Demographers have shown that this strategy will have a limited impact on societal disease burden because delaying 1 disease still exposes one to the exponentially increasing risks of all other age-related diseases. Currently, pharmaceutical agents including metformin and analogs of rapamycin are being considered for human trials to test this idea.11,12 How does one select end points to show that the biology of aging has been affected without following thousands of people for several years to observe rates of incident disease and death? There is a great deal of effort being devoted to identifying potential blood-based biomarkers that might serve as plausible indicators of the aging process for use in such trials. Of relevance to this discussion, IL-6, cystatin C, and NT-proBNP have all been proposed as potential trial biomarkers.13 All 3 increase with age, predict mortality and function across their entire ranges, and have been shown to be responsive to intervention. NT-proBNP is produced by the stressed heart and has been shown to be related to the risk of a number of different cardiovascular disease outcomes, including heart failure, myocardial infarction, sudden cardiac death, and arrhythmia, but its consideration as a potential aging biomarker is new. Intriguingly, recent data from the PLATO biomarkers study (Platelet Inhibition and Patient Outcomes trial) found that a 1-log-unit SD difference in baseline NT-proBNP was related to a 2.21-fold increase in the rate of nonvascular mortality in patients with acute coronary syndromes.14 Thus, it is possible that the relationships with the biomarkers measured by Kuh and colleagues and function may reflect underlying biological age, which would also be reflected in diminished physical capacity.As a researcher who started his career in cardiovascular epidemiology and has since migrated to aging research, I find the paper by Kuh and colleagues wonderful to see. It touches on 2 themes of growing importance: the role of physical function assessment in cardiovascular research, and the place of cardiovascular pathophysiology in the context of organismal aging. One hopes that this paper is an indicator of increasing attention toward these important themes within the cardiovascular research community.DisclosuresNone.FootnotesThe opinions expressed in this article are not necessarily those of the editors or of the American Heart Association.https://www.ahajournals.org/journal/circGuest editor for this article was Daniel Forman, MD.Stephen B. Kritchevsky, PhD, Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157. Email [email protected]eduReferences1. Kuh D, Cooper R, Sattar N, Welsh P, Hardy R, Ben-Shlomo Y. Systemic inflammation and cardio-renal organ damage biomarkers in middle age are associated with physical capability up to 9 years later: findings from a British birth cohort study.Circulation. 2019; 139:1988–1999. doi: 10.1161/CIRCULATIONAHA.118.037332LinkGoogle Scholar2. Guralnik JM, Ferrucci L, Pieper CF, Leveille SG, Markides KS, Ostir GV, Studenski S, Berkman LF, Wallace RB. Lower extremity function and subsequent disability: consistency across studies, predictive models, and value of gait speed alone compared with the short physical performance battery.J Gerontol A Biol Sci Med Sci. 2000; 55:M221–M231. doi: 10.1093/gerona/55.4.M221CrossrefMedlineGoogle Scholar3. Ferreira JP, Metra M, Anker SD, Dickstein K, Lang CC, Ng L, Samani NJ, Cleland JG, van Veldhuisen DJ, Voors AA, Zannad F. Clinical correlates and outcome associated with changes in 6-minute walking distance in patients with heart failure: findings from the BIOSTAT-CHF study.Eur J Heart Fail. 2019; 21:218–226. doi: 10.1002/ejhf.1380CrossrefMedlineGoogle Scholar4. Nagi S. Some conceptual issues in disability and rehabilitation.Sussman M, ed. In: Sociology and Rehabilitation. Washington, DC: American Sociological Association; 1965:100–113.Google Scholar5. World Health Organization. Towards a Common Language for Functioning, Disability and Health: ICF. Geneva, Switzerland: World Health Organization; 2002. https://www.who.int/classifications/icf/icfbeginnersguide.pdf. Accessed February 10, 2019.Google Scholar6. Forman DE, Arena R, Boxer R, Dolansky MA, Eng JJ, Fleg JL, Haykowsky M, Jahangir A, Kaminsky LA, Kitzman DW, Lewis EF, Myers J, Reeves GR, Shen WK; American Heart Association Council on Clinical Cardiology; Council on Cardiovascular and Stroke Nursing; Council on Quality of Care and Outcomes Research; and Stroke Council. Prioritizing functional capacity as a principal end point for therapies oriented to older adults with cardiovascular disease: a Scientific Statement for Healthcare Professionals from the American Heart Association.Circulation. 2017; 135:e894–e918. doi: 10.1161/CIR.0000000000000483LinkGoogle Scholar7. Kritchevsky SB, Forman DE, Callahan K, Ely EW, High KP, McFarland F, Pérez-Stable EJ, Schmader K, Studenski S, Williams J, Zieman S, Guralnik JM. Pathways, contributors, and correlates of functional limitation across specialties: workshop summary.J Gerontol A Biol Sci Med Sci. 2019; 74:534–543. doi: 10.1093/gerona/gly093CrossrefMedlineGoogle Scholar8. Kritchevsky SB, Williamson J. Putting function first.J Nutr Health Aging. 2014; 18:467–468. doi: 10.1007/s12603-014-0456-xCrossrefMedlineGoogle Scholar9. Abdul-Jawad Altisent O, Puri R, Regueiro A, Chamandi C, Rodriguez-Gabella T, Del Trigo M, Campelo-Parada F, Couture T, Marsal JR, Côté M, Paradis JM, DeLarochellière R, Doyle D, Mohammadi S, Dumont E, Rodés-Cabau J. Predictors and association with clinical outcomes of the changes in exercise capacity after transcatheter aortic valve replacement.Circulation. 2017; 136:632–643. doi: 10.1161/CIRCULATIONAHA.116.026349LinkGoogle Scholar10. Barzilai N, Cuervo AM, Austad S. Aging as a biological target for prevention and therapy.JAMA. 2018; 320:1321–1322. doi: 10.1001/jama.2018.9562CrossrefMedlineGoogle Scholar11. Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a tool to target aging.Cell Metab. 2016; 23:1060–1065. doi: 10.1016/j.cmet.2016.05.011CrossrefMedlineGoogle Scholar12. Mannick JB, Morris M, Hockey HP, Roma G, Beibel M, Kulmatycki K, Watkins M, Shavlakadze T, Zhou W, Quinn D, Glass DJ, Klickstein LB. TORC1 inhibition enhances immune function and reduces infections in the elderly.Sci Transl Med. 2018; 10:eaaq1564. doi: 10.1126/scitranslmed.aaq1564CrossrefMedlineGoogle Scholar13. Justice JN, Ferrucci L, Newman AB, Aroda VR, Bahnson JL, Divers J, Espeland MA, Marcovina S, Pollak MN, Kritchevsky SB, Barzilai N, Kuchel GA. A framework for selection of blood-based biomarkers for geroscience-guided clinical trials: report from the TAME Biomarkers Workgroup.Geroscience. 2018; 40:419–436. doi: 10.1007/s11357-018-0042-yCrossrefMedlineGoogle Scholar14. Lindholm D, James SK, Gabrysch K, Storey RF, Himmelmann A, Cannon CP, Mahaffey KW, Steg PG, Held C, Siegbahn A, Wallentin L. Association of multiple biomarkers with risk of all-cause and cause-specific mortality after acute coronary syndromes: a secondary analysis of the PLATO biomarker study.JAMA Cardiol. 2018; 3:1160–1166. doi: 10.1001/jamacardio.2018.3811CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Kritchevsky S and Kaskie B (2019) Is Old Age or Aging a Disease, in a Literal or a Metaphorical Sense?, Public Policy & Aging Report, 10.1093/ppar/prz021, 29:4, (123-125), Online publication date: 11-Oct-2019. Related articlesSystemic Inflammation and Cardio-Renal Organ Damage Biomarkers in Middle Age Are Associated With Physical Capability Up to 9 Years LaterDiana Kuh, et al. Circulation. 2019;139:1988-1999 April 23, 2019Vol 139, Issue 17 Advertisement Article InformationMetrics © 2019 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.119.039116PMID: 31013138 Originally publishedApril 23, 2019 KeywordsEditorialsPDF download Advertisement" @default.
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