Frailty and Its Potential Relevance to Cardiovascular Care

Abstract

Frailty is characterized by vulnerability to acute stressors and is a consequence of decline in overall function and physiologic reserves. An estimated 7% of the US population older than 65 years and 30% of octogenarians are frail. The domains to define frailty include mobility, strength, balance, motor processing, cognition, nutrition, endurance, and physical activity. Pathophysiologic pathways leading to frailty involve a multisystem cascade that includes neuroendocrine dysfunction with lower insulinlike growth factor and dehydroepiandrosterone sulfate and an altered inflammatory milieu with increased levels of C-reactive protein, interleukins, tumor necrosis factor α, and abnormal coagulation. Frailty predicts death and heralds the transition to disability in general populations. As the population with coronary artery disease shifts toward older patients, physicians must consider the role of frailty in their patients. This review will enable clinicians to recognize frailty and consider its relevance in their daily practice. We also elaborate on reasons to consider frailty in older adults with cardiovascular disease and focus on its early identification, on referral to specialists, and on care after serious cardiac events.

During the past century, the average life expectancy has lengthened, resulting in a larger older population presenting with acute and chronic cardiovascular diseases. Variation in the health status of older patients is apparent, ranging from robust to frail. An estimated 7% of the US population older than 65 years and 30% of octogenarians are frail.¹ Frailty, a construct well described and debated in the geriatric literature, is characterized by vulnerability to acute stressors and is a consequence of decline in overall function and physiologic reserves. Frail patients have a reduced ability to maintain homeostasis in the face of acute stress. Cardiovascular practice guidelines acknowledge the importance of global health status in older adults, stating that decisions on management in the elderly should reflect considerations of general health, comorbidities, cognitive status, and life expectancy.^2-4As the population with coronary artery disease (CAD) ages, cardiologists must be ready to consider the role of frailty in their patients.⁵ In light of this situation, this review examines the definitions, incidence and prevalence, proposed pathophysiologic pathways, and outcomes associated with frailty. In so doing, it will enable clinicians to recognize frailty and consider its relevance in their daily practice.

English-language publications in PubMed and references from relevant articles published between 1970 and 2007 were reviewed. Main search terms were frailty, comorbidity, falls, endocrine or inflammatory markers of frailty, and sarcopenia. Articles were selected on the basis of quality, relevance to the central concept of frailty, importance in illustrating a proposed pathophysiology, or the level of attention that they had previously received in the field.

FRAILTY AS A CONCEPT

From observing people who have aged successfully, it is apparent that chronological age correlates loosely with biological age.⁶ This was highlighted in a population of older adults, in which adjustment for 27 biological risk factors including comorbidity, social status, lifestyle and disease factors, cognition, and frailty substantially reduced the association between chronological age and 5-year mortality (ages 80-84 years: unadjusted relative risk, 4.1; adjusted relative risk, 1.7).⁷ This suggests that factors beyond age explain much of the increased mortality associated with age. There is growing recognition that a biological state, referred to as frailty, affects older populations.

Although the definition of frailty continues to evolve, its hallmark is decreased resistance to stressors. All organisms start out with redundancy of structure and function, which serves them well during environmental stresses. A review of human bodily systems reveals that one third of organ capacity is adequate for normal organ function.⁸ The remaining reserves of organ function vary according to lifetime exposures to injury and illness. As the biological reserves are diminished, any challenge can exceed the capacity for recovery. Those without remaining buffers are prone to negative health outcomes, such as disability and death (Figure 1).⁹ The limited reserves could easily become apparent only when a stressful event (such as acute cardiac illness) unmasks them, as in myocardial infarction. Frailty is distinct from the related concepts of comorbidity, defined as the burden of coexisting medical illnesses, and disability, the limited ability for self-care.¹⁰ These distinctions are paramount and are elaborated further in this review.

FIGURE 1.

Trajectories of health and functioning. Full performance = high functional reserve that allows patients to face environmental perturbations with ease; frailty = patients are at high risk of homeostasis disruption and consequent negative health outcomes, including disability and death, probably from exhaustion of functional reserve. From J Endocrinol Invest,⁹ with permission from the Italian Society of Endocrinology.

^a Can be physical, cognitive, social, or quality of life.

FRAILTY DEFINITIONS

There is no single best definition of frailty, as this construct is a constellation of clinical attributes. Frailty does not fit easily with the typical organ-specific model of disease. The frailty phenotype represents the complex relationship among sarcopenia, physical activity, nutritional intake, and energy expenditure. Sarcopenia leads to poor muscle strength, which limits mobility and physical activity, thereby reducing energy expenditure and nutritional intake. This leads in turn to weight loss and worsening sarcopenia. In 2001, investigators from Johns Hopkins developed a conceptual framework of frailty combining attributes of body composition, nutrition, and mobility into an explanatory pathophysiologic phenotype (Figure 2).¹ Table 1 lists some other definitions as well.^1,11-17

FIGURE 2.

Cycle of frailty combines elements of body composition, nutrition, and mobility into a pathophysiologic pathway. In this pathway, sarcopenia and poor muscle strength, by limiting mobility and physical activity, reduce total energy expenditure and nutritional intake, thereby causing weight loss and further sarcopenia. In defining frailty, involvement of musculoskeletal system is central and paramount. Loss of movement capacity frequently accelerates decline in other organ systems. From J Gerontol A Biol Sci Med Sci,¹ with permission of the Gerontological Society of America. Copyight © 2001.

TABLE 1.

Prevalence, Incidence, and Various Definitions of Frailty^a

Reference	Prevalence (%)	Incidence (%)	Data source	Measure of frailty
Fried etal,1 2001	6.9	4-y, 7.2	CHS	Gait speed, weight loss, physical activity, exhaustion, grip strength
Newman etal,11 2001	11.0	NA	CHS	Same as above
Jumadilova et al,12 2005	30.0	NA	Nursing home residents	Urinary incontinence
Holroyd-Leduc et al,13 2004	14.8	NA	AHEAD study	Urinary incontinence
Studenski etal,14 2004	NA	NA	CGIC-PF instrument	Six intrinsic and 7 consequence domains
Jones et al,15 2004	17.0, mild	NA	MGAT trial	FI-CGA, comprising 10 standard domains
	58.0, moderate
	25.0, severe
Puts et al,16 2005	19.0	14.1	LASA	Nine frailty markers: body weight, peak expiratory flow, cognition, vision and hearing problems, incontinence, sense of mastery, depressive symptoms, and physical activity
Woods etal,17 2005	16.3	14.8	WHI observational study	Criteria for frailty same as proposed by Fried et al1

^aAHEAD = Asset and Health Dynamics Among the Oldest Old; CGIC-PF = Clinical Global Impression of Change in Physical Frailty; CHS = Cardiovascular Health Study; FI-CGA = Frailty Index-Complete Geriatric Assessment; LASA = Longitudinal Aging Study Amsterdam; MGAT = Mobile Geriatric Assessment Team; NA = not available; WHI = Women's Health Initiative.

Previously, health care professionals relied on subjective assessments to identify frailty, but a recent consensus report lists 8 domains in this phenotype: mobility, strength, balance, motor processing, cognition, nutrition, endurance, and physical activity.⁴ Performance measurements of muscle strength, such as grip strength and gait speed, are included with clinical history and functional status measures. Performance assessment identifies variations in strength at or below the level of daily function. This is important because sarcopenia, defined as age-related decline in lean muscle mass, is a key component of the frailty phenotype. During a person's lifetime, muscle strength and muscle mass are highest in the teen years and begin to decrease after age 30 years. After age 50 years, muscle strength decreases at a rate of 10% to 15% per decade of life, paralleled by a decline in the number of fast-twitch fibers.^18-20

INCIDENCE AND PREVALENCE

Multiple definitions for frailty have resulted in varying estimates of its prevalence. The prevalence of frailty in the recent Longitudinal Aging Study Amsterdam (LASA) involving 1720 community-dwelling adults older than 65 years was 19%¹⁶; however, it was 6.9% in the older Cardiovascular Health Study (CHS) that used different criteria (Table 2).¹ Differences in the populations (communitydwelling residents vs nursing home residents) and age ranges (>65 years to centenarians) also limit estimates. There is a paucity of data on frailty in cardiovascular populations. In contrast to the overall CHS group, subgroups with cardiovascular disease had higher prevalence of frailty.¹¹ In 2 small prospective studies, frailty, as defined by the CHS criteria, was observed in 20% of older patients (≥65 years) undergoing percutaneous coronary interventions²¹ and 27% of older patients (≥70 years) with serious CAD at cardiac catheterization.²²

TABLE 2.

Definition of Frailty as Proposed by the Cardiovascular Health Study

Unintentional weight loss	4.5 kg in the past year
Exhaustion	CES-D
Physical activity	Minnesota Leisure Time Activity questionnaire
Walk time	Cutoff for time to walk 4.6 m criteria
Men, stratified by height
≤173 cm	≥7 s
≤173 cm	≤6 s
Women
≤159cm	≥7 s
>159cm	≤6 s
Grip strength	Cutoff for grip strength (kg)
Men, stratified by BMI	criterion for frailty
≤24.0	≤29.0
24.1-26.0	≤30.0
26.1-28.0	≤30.0
>28.0	≤32.0
Women, stratified by BMI
≤23.0	≤17.0
23.1-26.0	17.3
26.1-29.0	18.0
>29.0	21.0
Frailty	3 or more core elements
Intermediate frailty (prefrail)	1 or 2 core elements

^aBMI = body mass index; CES-D = Center for Epidemiologic Studies Depression Scale.

Data from J Gerontol A Biol Sci Med Sci.¹

FRAILTY AND COMORBIDITY

The distinction between frailty and comorbidity is paramount despite overlap between constructs of comorbid conditions, frailty, and disability as demonstrated in the CHS population.¹⁰ Of 2576 patients with comorbidity, 249 were frail. Frail patients were more likely to have a history of cardiovascular disease (31% vs 15%), chronic heart failure (14% vs 1%), diabetes (32% vs 19%), and hypertension (49% vs 37%) than their counterparts who were not frail.²³ In addition to higher prevalence of cardiovascular disease, frail elderly patients had more subclinical cardiovascular disease identified by carotid ultrasonography, electrocardiography, and echocardiography and had more infarct-like lesions visible on brain magnetic resonance imaging.¹¹ In a separate study, the presence of CAD was associated with a greater likelihood of subsequent decline in gait speed over time, a major factor in the frailty phenotype.²⁴ Weakness and exhaustion, characteristics of frailty, are symptoms of heart disease as well.²⁵ Additionally, exacerbation of heart disease can unmask frailty.

BIOLOGICAL UNDERPINNINGS OF FRAILTY

The “cycle of frailty” (Figure 2) describes a multisystem cascade that includes neuroendocrine dysfunction with lower insulinlike growth factor (IGF) and dehydroepiandrosterone sulfate and an altered inflammatory milieu with increased levels of C-reactive protein (CRP), interleukins, tumor necrosis factor α, and abnormal coagulation.^1,26 There are several reasons to suspect inflammatory and endocrine links with frailty. First, inflammatory markers (such as interleukin-6 and CRP) are elevated with normal aging, doubling between ages 40 and 65 years.⁹ The exact stimuli for higher inflammatory markers with aging are not well known and could reflect a rising burden of tissue damage, acute or chronic infection, or general deterioration in homeostatic mechanisms for repair.^27-30 Second, high levels of such markers are also associated with cardiovascular events and mortality.³¹ Several studies have linked elevated levels of CRP with future incident adverse cardiovascular events.³² A common denominator for frailty and cardiovascular disease could be higher levels of inflammatory markers (eg, CRP). Therefore, studies of how frailty, inflammation, and CAD are related are needed. Third, high levels of cytokines can induce skeletal muscle loss and neuroendocrine dysregulation.³³ Despite interesting theoretical links, the data on biomarkers in frailty are cross-sectional and preliminary (Table 3).^16,34-40

TABLE 3.

Biomarkers and Frailty^a

Reference	Biomarkers studied	Data source	Observations in frailty
Semba et al,34 2005	CD4+andCD8+ T cells	Women's Health and Aging Studies	CD8+ and CD28- higher
Leng et al,35 2004	IGF-1, DHEA-S, IL-6	Community-dwelling adults	IGF-1 and DHEA-S lower
Leng et al,36 2004	IL-6, TNF-α, andIL-10	Community-dwelling adults	Lower LPS-induced PBMC proliferation ratio and higher IL-6
Cohen et al,37 2003	IL-6 and D-dimer measurement	Duke Established Populations for Epidemiologic Studies of the Elderly	Highest levels of IL-6 and D-dimer had increased mortality
Bruunsgaard et al,38 2003	TNF-α and IL-6 measurement	Danish Centenarian Study	TNF-α: an independent prognostic marker for mortality
Walston et al,39 2002	CRP, fibrinogen, factors VII and VIII	Cardiovascular Health Study	Higher CRP, fibrinogen, factor VIII, and D-dimer in frail patients
van den Biggelaar et al,40 2004	LPS-induced IL-1β, IL-6, TNF-α, IL-1RA, IL-10	Leiden 85-plus study	Low levels of LPS-induced markers associated with higher mortality
Puts et al,16 2005	25(OH)D, CRP, IL-6, and IGF-1	LASA	Low 25(OH)D associated with prevalent/incident frailty; elevated CRP with incident frailty

^aCRP = C-reactive protein; DHEA-S = dehydroandrosterone sulfate; IGF = insulinlike growth factor; IL = interleukin; LASA = Longitudinal Aging Study Amsterdam; LPS = lipopolysaccharide; 25(OH)D = 25-hydroxyvitamin D; PBMC = peripheral blood mononuclear cells; TNF = tumor necrosis factor.

The role of hormones in frailty has also been studied. In studies of longitudinal aging, free testosterone index, IGF, and physical activity were predictors of sarcopenia.^41,42 In the Women's Health and Aging Study, low IGF-1 levels were associated with poor knee extensor muscle strength, slow movement, and difficulty with mobility.⁴³ Despite low hormone levels in frail individuals, replacement hormones have not been shown to be useful.⁴⁴ In a 2-year placebo-controlled, randomized trial involving 144 elderly men and women, neither dehydroepiandrosterone sulfate nor low-dose testosterone replacement had any physiologically relevant beneficial effects on body composition, physical performance, insulin sensitivity, or quality of life.⁴⁴ More recently, meta-analyses suggested that testosterone/dihydrotestosterone therapy produced a moderate increase in muscle strength in men participating in 11 randomized trials.⁴⁵ Testosterone supplementation during 6 months in older men with a low normal testosterone concentration did not affect functional status or cognition but increased lean body mass and had mixed metabolic effects.

Alterations in the biological milieu have associations with frailty, but these links remain theoretical; research is needed to elucidate the biological mechanisms contributing to the development and worsening of frailty.

EFFECT OF FRAILTY ON OUTCOMES

Patient-reported functional status and comorbid conditions are prognostic determinants of death in cardiovascular populations.^23,46,47 Frailty predicts death and heralds the transition to disability in general populations.⁴⁸ In the Women's Health Initiative, frail patients were almost twice as likely to die as patients not determined to be frail.¹⁷ Among 1720 respondents in LASA, 5-year mortality in men with frailty was 50% as compared with 15% in nonfrail men; findings were similar in women (Figure 3).^16,49 Frailty also predicts falls, poor function for activities of daily living (ADL), and hospitalization. In the Canadian comprehensive sampling of 9008 community residents stratified by age, a dose-response association between frailty and subsequent institutionalization and death was observed (Figure 4).^50,51 Frailty predicts adverse outcomes incrementally and independently from coexisting medical conditions. In a prospective cohort study of 5886 older adults, objective measures of subclinical disease and disease severity were independent and joint predictors of 5-year mortality (12%), along with male sex, relative poverty, physical activity, smoking, indicators of frailty, and disability.⁷ The Health and Retirement Study used the 1998 wave of 11,701 persons older than 50 years and incorporated both comorbid conditions and functional measures to develop and validate a prognostic index for 4-year mortality.⁵² Data are sparse on the prognostic relevance of frailty on CAD events. Two studies from the Cooperative Cardiovascular Project found frailty (defined as urinary incontinence, inability to walk, and low body mass index) to be a predictor of 1-year mortality and stroke after acute myocardial infarction.^53,54

FIGURE 3.

The Longitudinal Aging Study Amsterdam demonstrated poor survival rates among both men and women who were frail according to 9 frailty markers defined as static or dynamic and who consisted of 2257 respondents participating in 2 cycles: T1 in 1992-1993 and T2 in 1995-1996. A, Survival according to frailty status at T2. B, Survival according to frailty status at T1-T2. Fom J Am Geriatr Soc,⁴⁹ with permission from Wiley-Blackwell Publishing.

FIGURE 4.

Canadian comprehensive sampling of 9008 community residents. Adjustments have been made for age and sex. Frailty scale in this study is based on geriatric status scale and demonstrates dose-response relationship between grades of frailty and subsequent institutionalization and death. 0 = those who walk without help, perform activities of daily living (ADL), are continent, and are not cognitively impaired; 1 = those with bladder incontinence only; 2 = those with 1 (2 if incontinent) or more of the following: need for assistance with mobility or ADL, cognitive impairment with dementia, or bowel or bladder incontinence; 3 = those with 2 (3 if incontinent) or more of totally dependent for transfers or 1 or more ADL, incontinence of bowel and bladder, and diagnosis of dementia. From The Lancet,⁵⁰ with permission from Elsevier Limited.

RELEVANCE OF FRAILTY TO CARDIOVASCULAR CARE

Reasons to consider frailty in older adults with cardiovascular disease include its early identification, consideration of referral to specialists, and anticipation of care after major cardiac events. Although frailty definitions are useful in research, clinicians still rely on impressions to determine the vigor of individual patients. Yet frailty, and vulnerability that accompanies it, can be present before functional limitations or disability are apparent. Early recognition is hampered by the overlap with comorbidity and disability. Unintended weight loss, disability in ADLs or instrumental ADLs, and presence of multiple comorbid conditions in a complex cardiac patient should alert physicians to the possibility of associated frailty. Clinicians could screen older adults by performing simple tests, such as grip strength, gait speed, or quadriceps strength. Early recognition of advanced biological age would enable referral to a geriatric specialist, skilled in understanding the contributors to age-related declines, who could offer multidisciplinary interventions to slow or reverse the functional decline. Comprehensive geriatric assessments are geared to improving physical performance and quality of life. Many age-associated impairments are dynamic. In a community setting, up to 25% of elderly people who develop a new disability subsequently demonstrate full functional recovery. Assessment of psychosocial support after acute cardiac events can reduce admission to long-term care facilities.

Clinicians can also consider frailty in decision making. Accurate risk prediction has particular relevance to older adults because of unique risks, heterogeneity, and the value placed on preservation of independence. Assessing frailty can improve risk prediction in vulnerable patients who are elderly. Whereas treatment of frailty itself is limited, assessment can facilitate a multidisciplinary approach to care and direct greater attention to comorbid illnesses.

Early recognition of frailty is paramount, as it can enable identification of some treatable disorders associated with frailty, such as malignancy or major depression, and can allow physicians to discuss and introduce geriatric or palliative care approaches with patients and their families (Table 4). Timely recognition of early frailty can provide opportunities to ensure tailored, symptom-driven care geared toward improving the quality of life of elderly patients. Frailty can be arbitrarily divided into 3 stages— early, referring to the time of frailty recognition; middle, referring to the onset of functional decline; and late, referring to increasing functional decline, life-threatening illness, and imminent death.⁵⁵ Several therapeutic approaches are being studied in patients diagnosed as being frail. They include various forms of physical and strengthening exercises and nutritional or hormonal supplementation (eg, testosterone), especially in hormone-deficient elderly men.^56-60 The recognition, pathophysiology, and management of patients diagnosed as being frail is still evolving. With further insights into mechanisms and management, more concrete evidence-based guidelines will be available to aid in decision making about how to treat cardiac patients who meet criteria for frailty.

TABLE 4.

Key Points About Frailty

Frailty is an evolving concept without disease-based treatment or diagnosis It is characterized by a reduced ability to maintain or regain homeostasis in the face of perturbations and is distinct from comorbidities and disability

Frailty is associated with higher mortality, disability, and hospitalization in the cardiac population

Early recognition of frailty may enable referral to a geriatric specialist, anticipation of care, and the initiation of interventions to delay its progression

Decision making should consider the multidimensional health status of older adults, including the contribution of frailty

CONCLUSION

The aging of the population, with its high burden of vascular disease, will increase the number of older adults with cardiovascular disease and frailty. Some of the most troubling gaps in applying evidence-based treatments stem from a disconnect between biological and chronological age. Identifying impairment caused by aging in cardiovascular populations and its contribution to risk is thus of tremendous clinical importance. Safe, effective, equitable, and patient-centered health care can be achieved for this demographic group only by observing relevant outcomes within the framework of the multidimensional health issues of older adults.

Glossary

ADL

activities of daily living

CAD

coronary artery disease

CHS

Cardiovascular Health Study

CRP

C-reactive protein

IGF

insulinlike growth factor

LASA

Longitudinal Aging Study Amsterdam