SELF-CARE AND HEALTH OUTCOMES (T JAARSMA, SECTION EDITOR)

Frailty in Heart Failure

Izabella Uchmanowicz & Maria Łoboz-Rudnicka &

Przemysław Szeląg & Beata Jankowska-Polańska &

Krystyna Łoboz-Grudzień

# Springer Science+Business Media New York 2014

Abstract Considering the increasing age of individuals af-fected with heart failure (HF), a specific approach to theirtreatment is required, with more attention paid to geriatricconditions such as poor mobility, multiple disabilities, andcognitive impairment. Frailty is a distinct biological syndromereflecting decreased physiologic reserve and resistance tostressors. It was shown to occur frequently in patients withheart failure, with the prevalence ranging from 15 to 74 %,depending on the studied population and the method of as-sessment. We reviewed literature data on the influence offrailty, skeletal abnormalities, comorbidities and geriatric con-dition on diagnosis, treatment, and outcomes in elderly pa-tients with HF. Identification of frailty in patients with HF isimportant from the clinical point of view, as this conditionexerts unfavorable effects on the course of heart failure. Frailtycontributes to a higher frequency of visits to emergency de-partments, hospitalizations, and mortality in patients with HF.Exercise may improve mobility, and nursing support can beimplemented to help the patients adhere to medications.Therefore, frail patients should be diagnosed and treated ac-cording to available guidelines, and successfully educatedabout their condition.

Keywords Frailty . Cachexia . Sarcopenia . Comorbidities .

Heart failure . Prognosis

Introduction

The population of elderly people is growing, mostly due toimproved health care. As a consequence, a higher incidence ofheart failure (HF) has been observed as the prevalence of thiscondition increases with age. Elderly people (>65 years ofage) constitute over 80 % of the population of HF patients [1].Considering the increasing age of individuals with HF, aspecific approach to their treatment is required, with moreattention paid to geriatric conditions, such as poor mobility,multiple disabilities, and cognitive impairment. All of themsignificantly affect the course of HF, its treatment, and itsprognosis in older patients [2•, 3••].

As a part of the concept of frailty syndrome (FS), the term“frailty” has developed from the synonyms of advanced age,disability, and comorbidities to stand for a distinct biologicalsyndrome reflecting decreased physiologic reserve and resis-tance to stressors [3••, 4••, 5]. Frailty occurs more frequentlyamong patients with HF than among the general population,and serves as an independent predictor of visits to the emer-gency department, hospitalizations, and mortality [6, 7, 8•].This might be explained by the fact that frailty is associatedwith decreased mobility, tendency to fall, polypharmacy, co-morbidities, and cognitive and nutritional impairment [2•, 9].Furthermore, syndromes related to frailty, such as cachexiaand skeletal muscle abnormalities, are also associated withpoor prognosis.

Due to its prognostic role, the identification of frailtyis of crucial importance in patients with HF. Also, theidentification of individuals who are at an increased riskfor frailty is important as they may benefit from earlytherapeutic intervention. In this paper, we discuss theinfluence of frailty, skeletal abnormalities, comorbidities,and older age on diagnosis, treatment, and outcomes inelderly patients with HF.

I. Uchmanowicz (*) : B. Jankowska-PolańskaDepartment of Clinical Nursing, Wroclaw Medical University, K.Bartla 5, 51-616 Wroclaw, Polande-mail: izabella.uchmanowicz@umed.wroc.pl

M. Łoboz-Rudnicka : P. Szeląg :K. Łoboz-GrudzieńDepartment of Cardiology, T. Marciniak Memorial Hospital,Wroclaw, Poland

Curr Heart Fail RepDOI 10.1007/s11897-014-0198-4

Definitions and Tools for Identifying Frailty

Frailty is defined as a multidimensional physiological syn-drome, which mainly occurs in people over 65 years of age.Although several definitions of frailty have been proposedrecently, there is still not a single acceptable definition of thiscondition. One of the first FS definitions, still frequently usedin a clinical setting, was proposed in 2001 by Fried et al. [5],based on the Cardiovascular Health Study (CHS). The authorsidentified the biologic frailty phenotype, which incorporatessuch elements as body build, nutritional status, and psycho-motor status. Five physical indicators of FS—weight loss,sarcopenia, poor nutritional status, low level of physical ac-tivity, and the limitation of physical abilities—have beenidentified as risk factors for adverse outcomes in frail persons[5]. A consensus group consisting of delegates from interna-tional, European, and American societies defined frailty as “amedical syndrome with multiple causes and contributors thatis characterized by diminished strength, endurance and re-duced physiologic function that increased an individual’svulnerability to developing increased dependency and/ordeath” [3••].

A number of scientific tools that can identify frailty wereproposed, among them clinical tests, instrumental tests, andpatient self-report questionnaires [10–12]. The single-itemmeasures, like gait speed, handgrip strength, six-minute walkor timed up and go test, are widely used to screen for frailtyamong older adults [12, 13]. Two single items, gait speed andhandgrip strength, are listed among Fried’s criteria of frailty[5].

Currently, there are two approaches to FS. The first isrelated to the definition based on the FS phenotype proposedby Fried et al. [5]. The second derives from the deficit index,which allows us to determine the severity of FS through theverification of existing bio-psycho-social deficits [14], and theaccumulation of deficits, i.e., age-associated health disorders(symptoms, physical features, diseases, disability, abnormallaboratory test results). A high Frailty Index was identified asa predictor of mortality in a population observed for five years[14].

The latest definitions of FS are based on a multidimension-al concept in which frailty is a transitional state, dependent onvarious physical, psychological, and social factors that interactand disturb physiological balance. For example, the TilburgFrailty Indicator (TFI) is a self-administered instrument thattakes physical, psychological, and social aspects into account[15]. A simple questionnaire proposed by the InternationalAssociation of Nutrition and Aging, the so-called FRAILscale, evaluates the five components of fatigue, endurance,mobility, disorders, and weight loss as predictors of functionalstatus, hospitalization, and mortality rates [16].

To summarize, most instruments for the evaluation of“frailty” are based on FS phenotype and the FRAIL scale

[16], mainly focusing on physical aspects of the condition.Moreover, both the Frailty Index and the TFI take the psycho-logical and social aspects into account. The latest recommen-dation regarding frailty measures is included in the frailtyconsensus of 2013, which listed the Frail Scale, CHS, andTFI as well-validated instruments [3••].

Frailty and HF – Prevalence

Several studies documented an association between the FSand cardiovascular disease; this relationship is particularlystrong in the case of HF (Table 1). Frailty was shown to occurfrequently in patients with HF, with the prevalence rangingfrom 15 to 74 %, depending on the studied population and themethod of assessment [7, 8•, 17]. In a study of a Spanishpopulation with HF, frailty was found to be the most prevalentin patients ≥70 years and among women [17]. Although therisk of frailty increases with age, Lupon et al. [7] observed asignificant number (ca. 30 %) of relatively young (<70 years)frail persons in a population of HF patients.

A recent prospective Health, Aging and Body CompositionStudy [18] showed that FS constitutes an independent riskfactor for developing incident HF among older people. Otherstudies revealed that HF is often found in frail patients. In theCardiovascular Health Study [19], including a cohort of 5,201older adults, the prevalence of congestive HF was highest forfrail patients (14.0 % in the frail group vs. 4.6 % in theintermediate group vs. 1.8 % in the non-frail group, p<0.001). The Women’s Health Initiative Observational Study[20] showed that the prevalence of congestive HF at baselineis 6–7 times higher in frail than in non-frail patients (3.5 % vs.0.6 %, p<0.001); however, contrary to the history of coronaryheart disease, hypertension, or stroke, the history of conges-tive HF was not a risk factor for developing frailty statusduring observation.

Patients with HF are characterized by frequentrehospitalizations; according to Medicare data [21], one-fifthof patients with HF were rehospitalized within 30 days afterhospital discharge and one-third within 90 days. Heart failureaccounted for only 37 % of rehospitalizations, mostly causedby diseases other than HF, such as chronic obstructive pulmo-nary disease, renal failure, diabetes mellitus, or depression[22]. Among the geriatric conditions, slow gait and muscleweakness were independent predictors of hospital admissionin patients with HF [2•]. It is noteworthy that frailty constitutesan independent predictor of mortality in a population with HF.This may result from several reasons: frail patients suffer fromhigher number comorbidities and take more drugs. Moreover,they show cognitive dysfunction and less frequently use va-sodilators, i.e., agents that influence prognosis in HF [6].

Frailty may predispose to myocardial injury through re-duced resistance to stressors, such as coronary ischemia, or

Curr Heart Fail Rep

pressure and volume overload [4••], and consequently leads toa higher rate of HF decompensation and hospitalizations.

Frailty and HF – Common Pathological Pathways

The frequent coexistence of FS and HF probably results fromcommon pathological pathways that involve inflammatoryprocesses, and metabolic and autonomic disturbances. Inflam-mation is known to play an important role in the developmentof cardiovascular diseases (CVD), including HF. Moreover,inflammatory disturbances seem to be involved in the patho-genesis of frailty. Frail patients show elevated levels of in-flammation markers: white blood cells, interleukin 6, C-reactive protein, factor VIII, and fibrinogen, as well as bloodclotting markers, e.g., D-dimer [23]. Elevated concentrationsof inflammatory markers, especially TNF-α and its solublereceptors, lead to decline in muscle mass and strength, prob-ably through promoting catabolic processes in muscle cells[24].

Important evidence for the inflammatory nature of frailtywas provided by the results of the Women’s Health and AgingStudies I and II; the risk of frailty was shown to increase withthe number of coexisting inflammatory diseases, and is thehighest in presence of at least three of the following condi-tions: CVD, chronic kidney disease, anemia, pulmonary dis-ease, depressive symptoms, diabetes mellitus, peripheral ar-tery disease, or rheumatoid arthritis [25].

Another link between frailty and CVD may lead to endo-thelial dysfunction. The analysis of results from the ToledoStudy for Healthy Aging [26] revealed that endothelial func-tion, evaluated by asymmetric dimethylarginine levels, isimpaired in frail patients.

As mentioned before, autonomic dysfunction appears to bea common finding in both HF and frailty. Heart rate variabilitywas proven to be impaired in frail people [27]. The autonomicdysfunction contributes to decreased resistance to stressors inin frail individuals.

Sarcopenia, Cachexia and Frailty

Sarcopenia is considered to be a geriatric syndrome, charac-terized by loss of muscle mass and muscle strength; this inturn leads to increased disability, poor quality of life, and evendeath [28]. The European Working Group on Sarcopenia inOlder People (EWGSOP) [28] recommends that the diagnosisof sarcopenia be based on the incidence of both a decrease inmuscle mass and a decrease in muscle function, and proposesthe categorization of sarcopenia based on its cause—as pri-mary when no other causes are evident except ageing, andsecondary when it is related to other causes. Baumgartneret al. [29] observed the presence of sarcopenia in nearly halfof the surveyed population aged over 80 years. According toother authors, the prevalence of sarcopenia in people over theage of 60 ranges from 20 to 70 %, and is higher in men.

Sarcopenia is a symptom of frailty and plays a vital role inthe pathophysiology of this condition. One may expect thatsarcopenia should also be frequent in elderly patients withchronic HF. However, the current state of knowledge on thistopic is limited due to the lack of a simple and adequate test fordiagnosing sarcopenia. The IlSIRENTE study [30], involvinga population of frail older persons, showed that sarcopenia isassociated with increased mortality. Another study of musclewasting in patients with chronic HF (SICA-HF) [31] con-firmed that they suffer from a more advanced form of HF.

Cachexia, defined as “a complex metabolic syndrome as-sociated with underlying illness and characterized by loss ofmuscle with or without loss of fat mass”, is an independent,unfavorable prognostic factor in HF patients [32, 33]. Accord-ing to the European Society of Cardiology [34], cachexia isobserved in 10–15 % of persons with HF, especially in thosewith reduced ejection fraction. Moreover, the mortality inindividuals with chronic HF and cardiac cachexia is 2–3 timeshigher than in non-cachectic subjects with this condition [35].Anker et al. [36] identified cachexia as a strong independentrisk factor for mortality in patients with chronic HF, togetherwith a low peak-oxygen consumption. Importantly, manyclinical features of cachexia, namely fatigue, muscle

Table 1 Prevalence of frailty among patients with HF

Authors HF patients (n) Frailty (%) Outcome

Newman et al. [19] 181 23 % (intermediate frailty 54 %) Not studied

Cacciatore et al. [6] 120 15 % Increased mortality among patients with frailty on 12-year follow-up

Woods et al. [20] 509 45 % (intermediate frailty 28 %) Not studied

Altimir et al. [17] 360 41 % Not studied

Lupon et al. [7] 622 39.9 % Significant relationships between frailty and 1-year mortalityand 1-year rehospitalization rates

McNallan et al. [71•] 448 19 % (intermediate frailty 55 %) Frailty – an independent predictor of hospitalization

Curr Heart Fail Rep

weakness, sarcopenia, and inflammation, are also observed inthe course of the FS. However, while weight loss is crucial forthe diagnosis of cachexia, it is not necessarily associated withfrailty. Loss in muscle mass can be counterbalanced by anincrease in fat mass; this phenomenon is referred to assarcopenic obesity. Stephen and Janssen [37] revealed thatwhile sarcopenia and obesity alone do not modulate cardio-vascular risk, a diagnosis of sarcopenic obesity based ondecreased muscle strength can be associated with an increasedincidence of cardiovascular conditions.

Frailty, HF, and Comorbidities

Chronic diseases that coexist with another condition, in thiscase chronic HF, are referred to as comorbidities [38].Feinstein and Landis [39] defined comorbidity as “any distinctadditional entity that has existed or may occur during theclinical course of a patient who has the index disease understudy”. In turn, Guralnik [40] defined comorbidities as the co-occurrence of multiple diseases in one person. Although boththe conditions are common, one should distinguish betweenfrailty and multimorbidity.

In the Medicare study [22], 96 % of 22,630 patients olderthan 65 years of age with HF had at least one non-cardiaccomorbidity; 70 % had more than three comorbidities, and40 % showed over five co-existing conditions. According toBraunstein et al. [22], the risk of hospitalization increases withthe number of comorbidities. Ather et al. [41] showed that theprevalence of non-cardiac comorbidities in patients with HFand preserved left-ventricular ejection fraction (HFpEF) ishigher than in those with HF and reduced left-ventricularejection fraction (HFrEF); furthermore, the patients withHFpEF and a high overall burden of comorbidities had morenon-HF conditions than those with HFrEF. It is noteworthythat comorbidities overlap with disability and other geriatricsyndromes, such as frailty. All in all, comorbidity, disability,and frailty are not similar; they may occur alone or even leadto one another. Wong et al. [42] documented comorbidities in82 % of community-dwelling frail people. Many complexrelationships between HF, comorbidities, and FS can be ob-served. The symptoms of HF, such as reduced functionalcapacity, dyspnea, and fatigue, may accelerate muscle loss,which leads to sarcopenia; this, in turn, may constitute acomponent of FS. Moreover, frailty, comorbidities and dis-abilities were reported to overlap each other among CHSpatients [5].

The presence of frailty and multiple comorbidities signifi-cantly impedes or delays diagnosing HF in elderly patients.Furthermore, those conditions affect the course and treatmentof HF and may increase the risk of hospitalization or morbid-ity in this group.

HF and Cognitive Impairment

Cognitive impairment is common in older adults with HF. Theprevalence of this condition is estimated at about 25 % [2•].Several longitudinal studies on aging revealed that cognitiveimpairment constitutes a negative predictor of survival. Twomain pathophysiological mechanisms underlying the associa-tion between HF and cognitive impairment have been pro-posed: intermittent cerebral hypoperfusion and cerebralmicroemboli [9].

The International Consensus Group provided the first def-inition of cognitive frailty condition in older adults. Cognitionhas already been categorized as a component of frailty. Worsecognitive performance can be associated with an even two-fold increase in mortality [43]. This can result from problemsin recognizing symptoms of diseases, worse adherence totherapeutic interventions, and a lack of a healthy lifestyleamong persons with cognitive impairment [44].

Cognitive impairment may also affect an individual’s ac-tivities of daily living, with resultant functional progression ofthe condition. The risk of falling increases with cognitiveimpairment of frail individuals [9, 45, 46]. Compared to otherpopulations of HF patients, individuals with HF are at higherrisk of cognitive impairment and falls [9]. However, therelationship between cognitive impairment and falls is stillunclear. Some authors suggested that cognitive impairmentmay increase the risk of falling, affecting such functions asgait, balance, or stepping ability [47, 48].

Also, the risk of institutionalization increases proportional-ly to cognitive impairment. Several studies showed that age,cognitive disorders, functional decline, and the number ofprescriptions may be associated with the risk of institutional-ization among older people [49].

Frailty and HF—Diagnostic and Therapeutic Difficulties

Clinical assessment of elderly patients with HF is challenging,as common signs and symptoms of this condition, e.g., fa-tigue, decreased exercise endurance, dyspnea, and peripheraledema, may also result from a number of other comorbidities(e.g., diseases of the respiratory system, venous insufficiency),or be attributed to older age itself [50, 51]. Furthermore,fatigue and decreased exercise endurance are common amongelderly patients. Of the clinical symptoms, orthopnea andparoxysmal nocturnal dyspnea are regarded as the most usefulin recognizing HF [52]. Diagnosing HF in elderly patientsconstitutes a challenge for several reasons: unspecific symp-tom characteristics and the confounding effects of comorbid-ities, limited access to diagnostic tests, e.g., the measurementof natriuretic peptides, echocardiography, tissue Doppler orcardiac magnetic resonance, and the still underestimated

Curr Heart Fail Rep

prevalence of frailty with HFpEF with resultant therapeuticdifficulties [50].

Diagnosis of HF in elderly people requires objective as-sessment. Manzano et al. [52] proposed an algorithm fordiagnosing HF in the elderly. Management of patients withlow clinical probability of HF (assessed on the basis of clinicalsymptoms, ECG, and chest x-ray) should be determined bythe measurement of natriuretic peptides: HF can be excludedin the case of low levels of BNP (<100 pg/mL) or NT-proBNP (<400 pg/ml); in an opposite case, echocardiography isrecommended [52]. It is noteworthy that a lower threshold ofnatriuretic peptides for excluding frailty in stable patients(BNP <35 pg/ml, NT-proBNP <125 pg/ml) was defined inthe new 2012 ESC guidelines on the diagnosis and treatmentof HF [34].

Echocardiography plays a major role in the diagnosis ofHF: it differentiates between HFrEF and HFpEF; the latter istypical for elderly people, especially women, with a longhistory of hypertension and other comorbidities [53]. Theepidemiology of HFpEF, namely its higher incidence amongelderly people with comorbidities, raises questions about thecommon pathogenic pathways of this condition and frailty[54].

The difficulties of treating elderly frail patients with HF aremostly associated with the presence of multiple comorbiditiesand polypharmacy that predisposes them to a higher preva-lence of adverse drug effects. Complicated and, usually, de-layed diagnosis of HF in frail elderly patients results in thedelayed introduction of adequate, guideline-recommendedtreatment. This constitutes one of many problems related tothe HF therapy in frail people.

Frail patients are often perceived as prone to the side effectsof angiotensin receptor inhibitors, i.e., postural hypotensionand renal impairment, bradyarrhythmias observed during betablocker therapy, hyperkalemia and renal impairment inducedby aldosterone receptor antagonists, and urinal incontinenceand electrolyte imbalance resulting from diuretic treatment[50, 51]. Therefore, they usually do not receive complete HFtreatment, and prescribed doses of medications are muchlower than those recommended in the respective guidelines[50, 51]. Another important factor that limits the introductionof adequate HF therapy is polypharmacy and a fear of dan-gerous interactions with drugs used in treating comorbidities.Polypharmacy is frequent among elderly people; according toLien et al. [55], 90% of elderly people admitted to the hospitalwith the diagnosis of HF are taking at least four differentmedications.

Of the factors that complicate the management of frailpatients, non-compliance appears to be one of the most im-portant. Non-compliance may result from both cognitive andphysical impairment of frail persons. While the former causeimpairs the understanding of the therapeutic regimen, thelatter limits regular access to the doctor, laboratory, and

rehabilitation programs [51]. The issue of compliance is ofcrucial importance in frail patients with atrial fibrillation whorequire anticoagulation therapy. Strict adherence to the thera-peutic regimen is required in the case of anticoagulationagents, as any misuse may lead to life-threatening bleedingcomplications. Therefore, according to the 2013 expert con-sensus of the French Society of Geriatrics and Gerontologyand the French Society of Cardiology on the management ofatrial fibrillation in elderly people [56], the introduction ofanticoagulation treatment should be preceded by the assess-ment of cognitive function with the Mini Mental StateExamination.

Polypharmacy and Falls

The problem of falls in the population of elderly people iswidely discussed; recent studies also focus on falls in patientswith HF [57]. According to Agostini et al. [58], a risk of fallsin the elderly population increases proportionally to the num-ber of ingested drugs, and, as mentioned previously, frailtycan predispose to polypharmacy. Therefore, reduction ofpolypharmacy should be one objective of multidisciplinarycare. Ledwidge et al. [59] revealed that specialist care exertsbeneficial effects on the prevalence of polypharmacy amongpatients with HF, and Pulignano et al. [60] confirmed thepositive contribution of multidisciplinary care in a group ofpatients with HF and frailty. According to literature, interven-tions aimed at a reduction of polypharmacy should includeeducation of patients and their families by a doctor prescribingmedicines [61], and comprehensive geriatric evaluation ofelderly adults [2•].

Possible Therapeutic Intervention

Frailty consensus defined four possible treatments for FS:exercise (resistance and aerobic), caloric and protein support,vitamin D supplementation, and reduction of polypharmacy[3••]. As mentioned previously, cachexia is an importantcomorbidity in HF patients. Although there is no establishedtreatment for cardiac cachexia, available data refer to thefavorable effects of nutritional therapy, micronutrient supple-mentation, physical activity, neurohormonal blockade, immu-nomodulatory agents, anabolic steroids, and appetite stimula-tion [35, 62]. Physical and mental exercises are recommendedas well. Physical activity is the only way to prevent the loss ofmuscle strength [63]. In their meta-analysis, Davies et al. [64]revealed that the participation of HF patients in cardiac reha-bilitation reduces the number of hospitalizations due to thiscondition. Both long- and short-term rehabilitation programsimprove health-related quality of life.

Curr Heart Fail Rep

Other reports underline the therapeutic significance of tes-tosterone administration for the improvement of muscle func-tion and physical fitness [65]. The positive influence of tes-tosterone was also revealed for women and men with HF, inwhom supplementation with this hormone enhanced physicalefficiency, muscle tension and strength, and glucose metabo-lism [66].

Some studies of elderly people revealed that low levels ofvitamin D are associated with limited physical activity and ahigh frailty index, both in patients with and without HF [67].According to other reports, supplementation with vitamin Dhas a positive influence on muscle strength and balancingability, as shown by extended walking distance and reducedfrequency of falls [68].

The assessment of geriatric conditions should be taken intoconsideration when making therapeutic decisions and plan-ning post-hospital care. Physical therapy and exercise mayimprove mobility, and increased caregiver and nursing sup-port can be introduced to help patients with dementia adhereto medication regimens. Other methods for reducing weak-ness and fatigue, which accompany FS, include a diagnosisand treatment of depression. Lupon et al. [7] reported on asignificant relationship between frailty, the occurrence of de-pression, and mortality rate during a one-year observation ofheart HF.

Conclusion

The identification of frailty in the advanced-age populationplays an important role in making therapeutic decisions, aswell as the stratification of risk, in cardiovascular disorders.The American Heart Association and the Society of GeriatricCardiology [69] emphasized the role of frailty in cardiovas-cular disease. Current guidelines for managing HF do notincorporate routine assessment or managing the geriatric con-dition. In patients with HF, an assessment of the geriatriccondition should be performed on top of the assessment ofthe cardiac function.

Clinical management needs to incorporate functional ca-pacity, non-cardiac comorbidity, and standardized geriatrictools (functional capacity, cognitive impairment) in order todefine the impact of these factors on prognosis and therapeuticresponse. Improved management requires that frailty is in-cluded in the individual state of health. The identification offrailty in patients with HF is important from the clinical pointof view, as this condition exerts unfavorable effects on thecourse of heart failure. Frailty contributes to a higher frequen-cy of visits to emergency departments, hospitalizations, andmortality in patients with HF [7]. Exercise may improvemobility, and nursing support can be implemented to helpthe patients adhere to medication regimens. Therefore, pa-tients should be diagnosed and treated according to available

guidelines, and successfully educated about their condition[70].

Compliance with Ethics Guidelines

Conflict of Interest Izabella Uchmanowicz, Maria Łoboz-Rudnicka,Przemysław Szeląg, Beata Jankowska-Polańska, and Krystyna Łoboz-Grudzień2 declare that they have no conflicts of interest.

Human and Animal Rights and Informed Consent This article doesnot contain any studies with human or animal subjects performed by anyof the authors.

References

Papers of particular interest, published recently, have beenhighlighted as:• Of importance•• Of major importance

1. Go AS, Mozaffarian D, Roger VL, Benjamin EJ, Berry JD, BordenWB, et al. Heart disease and stroke statistics–2013 update: a reportfrom the American Heart Association. Circulation. 2013;127:e6–245.

2.• Chaudhry SI, Wang Y, Gill TM, Krumholz HM. Geriatric condi-tions and subsequent mortality in older patients with heart failure. JAm Coll Cardiol. 2010;55:309–16. This study, conducted in a largecohort of older individuals with heart failure, showed a strongassociation between geriatric condition and both short- and long-term mortality.

3.•• Morley JE, Vellas B, van Kan GA, Anker SD, Bauer JM, BernabeiR, et al. Frailty consensus: a call to action. J Am Med Dir Assoc.2013;14:392–7. In this paper, a consensus group including dele-gates from international, European, and American societies, de-fined the term of frailty.

4.•• Afilalo J, Alexander KP,MackMJ,Maurer MS, Green P, Allen LA,et al: Frailty assessment in the cardiovascular care of older adults. JAm Coll Cardiol 2014;63:747–62. The authors of this reviewsynthesized the existing body of evidence regarding frailty incardiovasculardisease and discussed on the perspectives ofincorporatingfrailty into clinical practice.

5. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C,Gottdiener J, et al. Frailty in older adults: evidence for a phenotype.J Gerontol A Biol Sci Med Sci. 2001;56:M146–56.

6. Cacciatore F, Abete P, Mazzella F, Viati L, Della Morte D,D'Ambrosio D, et al. Frailty predicts long-term mortality in elderlysubjects with chronic heart failure. Eur J Clin Investig. 2005;35:723–30.

7. Lupon J, Gonzalez B, Santaeugenia S, Altimir S, Urrutia A,Mas D,et al. Prognostic implication of frailty and depressive symptoms inan outpatient population with heart failure. Rev Esp Cardiol.2008;61:835–42.

8.• McNallan SM, Chamberlain AM, Gerber Y, Singh M, Kane RL,Weston SA, et al. Measuring frailty in heart failure: a communityperspective. AmHeart J. 2013;166:768–74. This paper presents thedeficit index as a feasible alternative to other methods of ascertain-ing frailty.

9. Dodson JA, Chaudhry SI. Geriatric conditions in heart failure. CurrCardiovasc Risk Rep. 2012;6:404–10.

10. de Vries NM, Staal JB, van Ravensberg CD, Hobbelen JS, OldeRikkert MG, Nijhuis-van der SandenMW. Outcome instruments to

Curr Heart Fail Rep

measure frailty: a systematic review. Ageing Res Rev. 2011;10:104–14.

11. Shulman KI, Pushkar Gold D, Cohen CA, Zucchero CA. Clock-drawing and dementia in the community: a longitudinal study. Int JGeriatr Psychiatry. 1993;8:487–96.

12. Wells JL, Seabrook JA, Stolee P, Borrie MJ, Knoefel F. State of theart in geriatric rehabilitation. Part I: review of frailty and compre-hensive geriatric assessment. Arch Phys Med Rehabil. 2003;84:890–7.

13. Studenski S, Perera S, Patel K, Rosano C, Faulkner K, Inzitari M,et al. Gait speed and survival in older adults. JAMA. 2011;305:50–8.

14. Rockwood K, Andrew M, Mitnitski A. A comparison of twoapproaches to measuring frailty in elderly people. J Gerontol ABiol Sci Med Sci. 2007;62:738–43.

15. Gobbens RJ, vanAssenMA, LuijkxKG, Schols JM. The predictivevalidity of the Tilburg Frailty Indicator: disability, health careutilization, and quality of life in a population at risk.Gerontologist. 2012;52:619–31.

16. Abellan van Kan G, Rolland Y, Bergman H, Morley JE,Kritchevsky SB, Vellas B. The I.A.N.A Task Force on frailtyassessment of older people in clinical practice. J Nutr HealthAging. 2008;12:29–37.

17. Altimir S, Lupon J, Gonzalez B, PratsM, Parajon T, Urrutia A, et al.Sex and age differences in fragility in a heart failure population. EurJ Heart Fail. 2005;7:798–802.

18. Khan H, Kalogeropoulos AP, Georgiopoulou VV, Newman AB,Harris TB, Rodondi N, et al. Frailty and risk for heart failure in olderadults: the health, aging, and body composition study. Am Heart J.2013;166:887–94.

19. Newman AB, Gottdiener JS, McBurnie MA, Hirsch CH, Kop WJ,Tracy R, et al. Associations of subclinical cardiovascular diseasewith frailty. J Gerontol A Biol Sci Med Sci. 2001;56:M158–66.

20. Woods NF, LaCroix AZ, Gray SL, Aragaki A, Cochrane BB,Brunner RL, et al. Frailty: emergence and consequences in womenaged 65 and older in the Women's Health Initiative ObservationalStudy. J Am Geriatr Soc. 2005;53:1321–30.

21. Jencks SF, Williams MV, Coleman EA. Rehospitalizations amongpatients in the Medicare fee-for-service program. N Engl J Med.2009;360:1418–28.

22. Braunstein JB, Anderson GF, Gerstenblith G, Weller W, NiefeldM,Herbert R, et al. Noncardiac comorbidity increases preventablehospitalizations and mortality among Medicare beneficiaries withchronic heart failure. J Am Coll Cardiol. 2003;42:1226–33.

23. Walston J, McBurnie MA, Newman A, Tracy RP, Kop WJ, HirschCH, et al. Frailty and activation of the inflammation and coagula-tion systems with and without clinical comorbidities: results fromthe Cardiovascular Health Study. Arch Intern Med. 2002;162:2333–41.

24. Schaap LA, Pluijm SM, Deeg DJ, Harris TB, Kritchevsky SB,Newman AB, et al. Higher inflammatory marker levels in olderpersons: associations with 5-year change in muscle mass and mus-cle strength. J Gerontol A Biol Sci Med Sci. 2009;64:1183–9.

25. Chang SS, Weiss CO, Xue QL, Fried LP. Association betweeninflammatory-related disease burden and frailty: results from theWomen's Health and Aging Studies (WHAS) I and II. ArchGerontol Geriatr. 2012;54:9–15.

26. Alonso-Bouzon C, Carcaillon L, Garcia-Garcia FJ, Amor-AndresMS, El Assar M, Rodriguez-Manas L. Association between endo-thelial dysfunction and frailty: the Toledo Study for Healthy Aging.Age. 2013;20:20.

27. Varadhan R, Chaves PH, Lipsitz LA, Stein PK, Tian J, WindhamBG, et al. Frailty and impaired cardiac autonomic control: newinsights from principal components aggregation of traditional heartrate variability indices. J Gerontol A Biol Sci Med Sci. 2009;64:682–7.

28. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T,Landi F, et al. Sarcopenia: European consensus on definition anddiagnosis: report of the European Working Group on Sarcopenia inOlder People. Age Ageing. 2010;39:412–23.

29. Baumgartner RN, Koehler KM, Gallagher D, Romero L,Heymsfield SB, Ross RR, et al. Epidemiology of sarcopeniaamong the elderly in New Mexico. Am J Epidemiol. 1998;147:755–63.

30. Landi F, Cruz-Jentoft AJ, Liperoti R, Russo A, Giovannini S,Tosato M, et al. Sarcopenia and mortality risk in frail older personsaged 80 years and older: results from ilSIRENTE study. AgeAgeing. 2013;42:203–9.

31. Fulster S, Tacke M, Sandek A, Ebner N, Tschope C, DoehnerW, et al. Muscle wasting in patients with chronic heart failure:results from the studies investigating co-morbidities aggravat-ing heart failure (SICA-HF). Eur Heart J. 2013;34:512–9.

32. Pureza V, Florea VG. Mechanisms for cachexia in heart failure.Curr Heart Fail Rep. 2013;10:307–14.

33. Evans WJ, Morley JE, Argiles J, Bales C, Baracos V, GuttridgeD, et al. Cachexia: a new definition. Clin Nutr. 2008;27:793–9.

34. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, BohmM,Dickstein K, et al. ESC Guidelines for the diagnosis and treatmentof acute and chronic heart failure 2012: the Task Force for theDiagnosis and Treatment of Acute and Chronic Heart Failure2012 of the European Society of Cardiology. Developed in collab-oration with the Heart Failure Association (HFA) of the ESC. EurHeart J. 2012;33:1787–847.

35. Anker SD, Laviano A, Filippatos G, John M, Paccagnella A,Ponikowski P, et al. ESPEN guidelines on parenteral nutrition: oncardiology and pneumology. Clin Nutr. 2009;28:455–60.

36. Anker SD, Ponikowski P, Varney S, Chua TP, Clark AL, Webb-PeploeKM, et al.Wasting as independent risk factor for mortality inchronic heart failure. Lancet. 1997;349:1050–3.

37. Stephen WC, Janssen I. Sarcopenic-obesity and cardiovasculardisease risk in the elderly. J Nutr Health Aging. 2009;13:460–6.

38. Lang CC,Mancini DM. Non-cardiac comorbidities in chronic heartfailure. Heart. 2007;93:665–71.

39. Feinstein AR, Landis JR. The role of prognostic stratification inpreventing the bias permitted by random allocation of treatment. JChronic Dis. 1976;29:277–84.

40. Guralnik JM. Assessing the impact of comorbidity in the olderpopulation. Ann Epidemiol. 1996;6:376–80.

41. Ather S, Chan W, Bozkurt B, Aguilar D, Ramasubbu K, ZachariahAA, et al. Impact of noncardiac comorbidities on morbidity andmortality in a predominantly male population with heart failure andpreserved versus reduced ejection fraction. J Am Coll Cardiol.2012;59:998–1005.

42. Wong CH, Weiss D, Sourial N, Karunananthan S, Quail JM,Wolfson C, et al. Frailty and its association with disability andcomorbidity in a community-dwelling sample of seniors inMontreal: a cross-sectional study. Aging Clin Exp Res. 2010;22:54–62.

43. Kelaiditi E, Cesari M, Canevelli M, van Kan GA, Ousset PJ,Gillette-Guyonnet S, et al. Cognitive frailty: rational and definitionfrom an (I.A.N.A./I.A.G.G.) international consensus group. J NutrHealth Aging. 2013;17:726–34.

44. Nguyen HT, Black SA, Ray LA, Espino DV, Markides KS.Cognitive impairment and mortality in older mexican americans.J Am Geriatr Soc. 2003;51:178–83.

45. Zuccala G, Marzetti E, Cesari M, Lo Monaco MR, Antonica L,Cocchi A, et al. Correlates of cognitive impairment among patientswith heart failure: results of a multicenter survey. Am J Med.2005;118:496–502.

46. Vogels RL, Scheltens P, Schroeder-Tanka JM, Weinstein HC.Cognitive impairment in heart failure: a systematic review of theliterature. Eur J Heart Fail. 2007;9:440–9.

Curr Heart Fail Rep

47. Lundin-Olsson L, Nyberg L, Gustafson Y. Attention, frailty, andfalls: the effect of a manual task on basic mobility. J Am GeriatrSoc. 1998;46:758–61.

48. Persad CC, Jones JL, Ashton-Miller JA, Alexander NB, GiordaniB. Executive function and gait in older adults with cognitive im-pairment. J Gerontol A Biol Sci Med Sci. 2008;63:1350–5.

49. Luppa M, Luck T, Weyerer S, Konig HH, Brahler E, Riedel-HellerSG. Prediction of institutionalization in the elderly. A systematicreview. Age Ageing. 2010;39:31–8.

50. Fuat A, Hungin AP, Murphy JJ. Barriers to accurate diagnosis andeffective management of heart failure in primary care: qualitativestudy. BMJ. 2003;326:196.

51. Murad K, Kitzman DW. Frailty and multiple comorbidities in theelderly patient with heart failure: implications for management.Heart Fail Rev. 2012;17:581–8.

52. Manzano L, Escobar C, Cleland JG, FlatherM. Diagnosis of elderlypatients with heart failure. Eur J Heart Fail. 2012;14:1097–103.

53. Lam CS, Donal E, Kraigher-Krainer E, Vasan RS. Epidemiologyand clinical course of heart failure with preserved ejection fraction.Eur J Heart Fail. 2011;13:18–28.

54. Paulus WJ, Tschope C. A novel paradigm for heart failure withpreserved ejection fraction: comorbidities drive myocardial dys-function and remodeling through coronary microvascular endothe-lial inflammation. J Am Coll Cardiol. 2013;62:263–71.

55. Lien CT, Gillespie ND, Struthers AD, McMurdo ME. Heart failurein frail elderly patients: diagnostic difficulties, co-morbidities,polypharmacy and treatment dilemmas. Eur JHeart Fail. 2002;4:91–8.

56. Hanon O, Assayag P, Belmin J, Collet JP, Emeriau JP, Fauchier L,et al. Expert consensus of the French Society of Geriatrics andGerontology and the French Society of Cardiology on the manage-ment of atrial fibrillation in elderly people. Arch Cardiovasc Dis.2013;106:303–23.

57. van Diepen S, Majumdar SR, Bakal JA, McAlister FA, EzekowitzJA. Heart failure is a risk factor for orthopedic fracture: apopulation-based analysis of 16,294 patients. Circulation.2008;118:1946–52.

58. Agostini JV, Han L, Tinetti ME. The relationship between numberofmedications andweight loss or impaired balance in older adults. JAm Geriatr Soc. 2004;52:1719–23.

59. LedwidgeM, Travers B, RyderM, Ryan E,McDonald K. Specialistcare of heart failure improves appropriate pharmacotherapy at theexpense of greater polypharmacy and drug-interactions. Eur J HeartFail. 2004;6:235–43.

60. Pulignano G, Del Sindaco D, Di Lenarda A, Tarantini L, Cioffi G,Gregori D, et al. Usefulness of frailty profile for targeting olderheart failure patients in disease management programs: a cost-effectiveness, pilot study. J Cardiovasc Med (Hagerstown).2010;11:739–47.

61. Martinez-Selles M, Garcia Robles JA, Munoz R, Serrano JA,Frades E, Dominguez Munoa M, et al. Pharmacological treatmentin patients with heart failure: patients knowledge and occurrence ofpolypharmacy, alternative medicine and immunizations. Eur JHeart Fail. 2004;6:219–26.

62. von Haehling S, Lainscak M, Springer J, Anker SD. Cardiaccachexia: a systematic overview. Pharmacol Ther. 2009;121:227–52.

63. Lefkovits M. Cardiac rehabilitation in patients with heart failure–isthere a treatment beyond pharmacotherapy, surgery and deviceimplantation? Ther Umsch. 2011;68:119–24.

64. Davies EJ, Moxham T, Rees K, Singh S, Coats AJ, EbrahimS, et al. Exercise training for systolic heart failure: Cochranesystematic review and meta-analysis. Eur J Heart Fail.2010;12:706–15.

65. Travison TG, Basaria S, Storer TW, Jette AM, Miciek R, FarwellWR, et al. Clinical meaningfulness of the changes in muscle per-formance and physical function associated with testosterone admin-istration in older men with mobility limitation. J Gerontol A BiolSci Med Sci. 2011;66:1090–9.

66. Caminiti G, Volterrani M, Iellamo F, Marazzi G, Massaro R, MiceliM, et al. Effect of long-acting testosterone treatment on functionalexercise capacity, skeletal muscle performance, insulin resistance,and baroreflex sensitivity in elderly patients with chronic heartfailure a double-blind, placebo-controlled, randomized study. JAm Coll Cardiol. 2009;54:919–27.

67. Boxer RS, Dauser DA, Walsh SJ, Hager WD, Kenny AM. Theassociation between vitamin D and inflammation with the 6-minutewalk and frailty in patients with heart failure. J Am Geriatr Soc.2008;56:454–61.

68. Bischoff-Ferrari HA, Dietrich T, Orav EJ, Hu FB, ZhangY, KarlsonEW, et al. Higher 25-hydroxyvitamin D concentrations are associ-ated with better lower-extremity function in both active and inactivepersons aged > or =60 y. Am J Clin Nutr. 2004;80:752–8.

69. Alexander KP, Newby LK, Cannon CP, Armstrong PW, GiblerWB, Rich MW, et al. Acute coronary care in the elderly, part I:Non-ST-segment-elevation acute coronary syndromes: a scientificstatement for healthcare professionals from the American HeartAssociation Council on Clinical Cardiology: in collaboration withthe Society of Geriatric Cardiology. Circulation. 2007;115:2549–69.

70. Jaarsma T. Inter-professional team approach to patients with heartfailure. Heart. 2005;91:832–8.

71.• McNallan SM, Singh M, Chamberlain AM, Kane RL, Dunlay SM,Redfield MM, et al. Frailty and healthcare utilization among pa-tients with heart failure in the community. JACC: Heart Failure.2013;1:135–41. The authors present the deficit index as a feasiblealternative to other methods of ascertaining frailty.

Curr Heart Fail Rep