JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 65, NO.

10, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER INC. http://dx.doi.org/10.1016/j.jacc.2014.12.040

Pre-Frailty and Risk of Cardiovascular

Disease in Elderly Men and Women
The Pro.V.A. Study

Giuseppe Sergi, MD, PHD,* Nicola Veronese, MD,* Luigi Fontana, MD, PHD,yzx Marina De Rui, MD,*
Francesco Bolzetta, MD,* Sabina Zambon, MD,k{ Maria-Chiara Corti, MD,# Giovannella Baggio, MD,**
Elena Debora Toffanello, MD, PHD,* Gaetano Crepaldi, MD, PHD,k Egle Perissinotto, SCD,yy Enzo Manzato, MD, PHD*k

ABSTRACT

BACKGROUND Frailty is an important risk factor for cardiovascular disease (CVD), but the impact of early, potentially
reversible stages of frailty on CVD risk is unknown.

OBJECTIVES This study sought to ascertain whether pre-frailty can predict the onset of CVD in a cohort of community-
dwelling, not disabled, elderly people.

METHODS A sample of 1,567 participants age 65 to 96 years without frailty or disability at baseline was followed for
4.4 years. Pre-frailty was defined as the presence of 1 or 2 modified Fried criteria (unintentional weight loss, low physical
activity level, weakness, exhaustion, and slow gait speed), and incident CVD as onset of coronary artery diseases, heart
failure, stroke, peripheral artery disease, or CVD-related mortality.

RESULTS During follow-up, 551 participants developed CVD. Compared with participants who did not become frail,
those with 1 modified Fried criterion (p ¼ 0.03) and those with 2 criteria (p ¼ 0.001) had a significantly higher risk of
CVD, even after adjusting for several potential confounders (traditional risk factors for CVD, inflammatory markers, and
hemoglobin A1c levels). Low energy expenditure (p ¼ 0.03), exhaustion (p ¼ 0.01), and slow gait speed (p ¼ 0.03) were
significantly associated with the onset of CVD, whereas unintentional weight loss and weakness were not.

CONCLUSIONS Our findings suggest that pre-frailty, which is potentially reversible, is independently associated with a
higher risk of older adults developing CVD. Among the physical domains of pre-frailty, low gait speed seems to be the
best predictor of future CVD. (J Am Coll Cardiol 2015;65:976–83) © 2015 by the American College of Cardiology
Foundation.

F railty is a geriatric syndrome reflecting a state

of reduced physiological reserve and in-
creased vulnerability to poor resolution of ho-
meostasis after a stressor event that occurs in 25% to
50% of elderly patients with cardiovascular disease
(CVD) (1,2). The frailty phenotype is also a strong
independent predictor of disability, hospital and
nursing home admission, poor surgical outcomes,
and mortality (3–6). Data from observational studies
show a significant correlation between frailty and
CVD morbidity and mortality in the elderly (7–9),
and assessing these patients for frailty has been

From the *Department of Medicine DIMED, Geriatrics Division, University of Padua, Padua, Italy; yDepartment of Clinical and
Experimental Sciences, Brescia University Medical School, Brescia, Italy; zDivision of Geriatrics and Nutritional Science and Center
for Human Nutrition, Washington University School of Medicine, St. Louis, Missouri; xCEINGE Biotecnologie Avanzate, Naples,
Italy; kNational Research Council, Aging Branch, Institute of Neuroscience, Padua, Italy; {Department of Medical and Surgical
Sciences, University of Padua, Padua, Italy; #Azienda Unità Locale Socio Sanitaria 16, Padua, Italy; **Division of Internal Medicine,
Azienda Ospedaliera, Padua, Italy; and the yyDepartment of Cardiac, Thoracic and Vascular Sciences, Unit of Biostatistics,
Epidemiology and Public Health, University of Padua, Padua, Italy. This study was funded by the Fondazione Cassa di Risparmio
di Padua e Rovigo, the University of Padua, the Azienda Unità Locale Socio Sanitaria 15 and 18 of the Veneto Region, the Intra-
mural Research Program of the National Institute on Aging, and the Veneto Region Research Project 104/02 (Dr. Corti). All authors
have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Sergi and Veronese
contributed equally to this paper.

Manuscript received July 19, 2014; revised manuscript received November 19, 2014, accepted December 16, 2014.
JACC VOL. 65, NO. 10, 2015
MARCH 17, 2015:976–83
found instrumental in refining their prognosis and
defining optimal care and treatment for elderly indi-
viduals (10).
Several metabolic and hormonal factors, some of
which have also been implicated in the pathogenesis of
CVD (e.g., chronic low-grade inflammation and insulin
resistance) (1,2), are responsible for the gradual bio-
logical and functional decline that marks the transition
from a state of robustness to pre-frailty and, ulti-
mately, to frailty and its complications (11). It has been
hypothesized that the early detection of a pre-frail
status may provide a window of opportunity for more
aggressive preventive or therapeutic interventions
that might contain disability, hospitalization, and
mortality (12,13). Few and contrasting data are avail-
able, however, on the possible association between
pre-frailty and CVD risk in elderly men and women
without CVD or disability (3,5).
SEE PAGE 984
The aim of this prospective study is to investigate
the impact of pre-frailty, defined using the 5 modified
Fried criteria (3) of: 1) unintentional weight loss; 2)
low physical activity level; 3) weakness; 4) exhaus-
tion; and 5) slow gait speed, on the risk of developing
CVD in a cohort of community-dwelling elderly in-
dividuals with no disabilities, CVD, cancer, or de-
mentia at baseline. We adopted a modified Fried scale
to ascertain pre-frailty because this is the most often
used frailty index (3) and it has consistently been
shown to predict disability and mortality in large co-
horts of elderly patients with and without CVD (4–9).
METHODS
STUDY POPULATION. This study was based on an
analysis of 4.4  1.2 years of follow-up data obtained in
the Progetto Veneto Anziani (Pro.V.A.) population-
based prospective cohort study conducted in 2 sepa-
rate geographic areas near the city of Padua in the
Veneto Region of Northern Italy. The study enrolled
3,099 age- and sex-stratified community-dwelling in-
dividuals age $65 years (1,854 women and 1,245 men)
from 1995 to 1997. Participants came from a random
sample of white men and women using a multistage
stratified method described elsewhere (14). After
excluding subjects with a diagnosis of CVD at baseline
(n ¼ 694), subjects with frailty (n ¼ 200) or any
disability in activities of daily living (n ¼ 499), and
subjects who declined to attend follow-up visits (n ¼
139), the final sample consisted of 1,567 Italian subjects.
At baseline and follow-up examinations, each
participant underwent a detailed structured inter-
view, clinical evaluation, and blood chemistry and
Sergi et al. 977
Pre-Frailty and CVD in the Elderly
performance-based tests to document an ABBREVIATIONS
extensive range of demographic, biological, AND ACRONYMS
and medical characteristics, with the support
ABI = ankle-brachial index
of standardized algorithms (14). Cognitive
BMI = body mass index
function was assessed with the 30-item
BP = blood pressure
Mini-Mental State Examination and depres-
sion with the Geriatric Depression Scale CI = confidence interval
(GDS) (15,16). Face-to-face interviews and CVD = cardiovascular disease
clinical assessments were performed by GDS = Geriatric
Depression Scale
trained physicians and nurses. The present
study was approved by the Human Studies HF = heart failure
Committee of Padua University and by HR = hazard ratio
the Veneto Region’s Local Health Units MI = myocardial infarction
No. 15 and No. 18. All subjects gave their informed
consent.
MEASUREMENTS. Body weight was measured on a
calibrated balance scale. Height was determined us-
ing a stadiometer to the nearest 0.5 cm. Waist
circumference was obtained by using a cloth tape,
with the waist defined as the mid-point between the
highest point of the iliac crest and the lowest part of
the costal margin in the mid-axillary line. Body mass
index (BMI) was calculated as: weight (in kilograms)/
height (in meters) squared. Blood pressure (BP) was
measured with a mercury sphygmomanometer
(Erkameter 300, Erka, Bad Tölz, Germany) in both
arms after the participant had been resting quietly for
>5 min in a seated position. For the ankle-brachial
index (ABI) test, systolic BP was measured with BP
cuffs on the right brachial artery and both posterior
tibial arteries. ABI was calculated as the ratio of the
average ankle systolic to arm systolic BP, taking the
lowest value for reference; a value <0.9 was used for
the diagnosis of peripheral artery disease (17).
Physical performance was assessed as follows:
 Short Physical Performance Battery, derived from 3
objective physical function tests (18). Each test was
scored from 0 (inability to complete the test) to 4
(highest level of performance). The scores from all
3 tests were summarized in a composite score of
0 to 12 with higher scores reflecting better physical
function.
1. Tandem test: Participants were asked to main-
tain their balance, progressing from having their
feet side-by-side to a semi-tandem and then
full-tandem position.
2. Gait speed: The best performance achieved in 2
walks at usual pace along a 4-m corridor was
recorded in meters per second. Participants
were allowed to use canes or walkers.
3. Chair stands time: Participants were asked to
stand up and sit down 5 times as quickly as
possible, with their hands folded across their
978 Sergi et al.
Pre-Frailty and CVD in the Elderly
chest. The time taken to complete the test was
recorded in seconds.
 Handgrip strength: Handgrip strength was me-
asured (in kilograms) using a JAMAR hand-held
dynamometer (BK-7498, Fred Sammons, Inc.,
Burr Ridge, Illinois). The best result obtained at 3
attempts on the dominant side was used for our
analyses.
Fried et al. (3) defined frailty using 5 measurable
items. In our study, weakness and slow gait speed
were respectively defined using the best handgrip
strength value and the best timed walk over 4 m at
usual pace, stratified by sex and BMI cutoffs, as
originally proposed by Fried et al. (3). Fried’s work
had yet to be published when our study was designed
(1995 to 1997), so the other 3 frailty items were
defined slightly differently. In our study, a low en-
ergy expenditure was defined as weekly physical
activity <383 kcal/week in males and <270 kcal/week
in females, calculated from the sum of all the leisure-
time activities performed during an ideal week in the
previous month; unintentional weight loss was
defined as a self-reported unintentional weight loss
>5 kg over the past year; and exhaustion was ascer-
tained by asking the question on the GDS scale, “Do
you feel full of energy?” Participants were considered
exhausted if they gave a negative answer and also
had a GDS score $10, as previously reported (19). A
modified version of the Fried index was consequently
used in our study.
Participants were classified as frail if they met 3 or
more of the 5 modified Fried criteria, as pre-frail if
they met 1 or 2, or as nonfrail if they met none of the
criteria. Subjects unable to perform the handgrip
strength or walking tests were considered as having
weakness or slow gait speed, respectively.
Coronary heart disease was defined as a history of
revascularization, hospitalization for myocardial
infarction (MI), electrocardiographic evidence of MI,
or self-reported history of MI or angina, accompanied
by the use of antianginal medication. Cerebrovascular
disease was defined as a documented (e.g., from
medical charts) history of stroke, transient ischemic
attack, or carotid endarterectomy, confirmed by an in-
depth neurological medical examination. Heart fail-
ure (HF) was defined on the basis of the participants’
history, physical examination, chest radiography, and
use of medication. An HF event was confirmed if, in
addition to a physician’s diagnosis, there were docu-
mented HF signs and symptoms; supporting findings
(e.g., pulmonary edema on radiograph); or HF
treatments were being used, including diuretics,
digitalis, angiotensin-converting enzyme inhibitors,
JACC VOL. 65, NO. 10, 2015
MARCH 17, 2015:976–83
or beta-blockers. Both at baseline and follow-up, the
physician performing the physical examination
diagnosed any CVD using all the previously listed
measures. Another cardiologist confirmed any CVD
diagnoses using a standardized algorithm considering
all the medical information collected on each partic-
ipant. Any disagreement was resolved by consensus
(14). In the follow-up assessment, CVD mortality
(codes from 390–459 according to International Clas-
sification of Diseases-9th Revision, 2002) was also
included. A copy of the official death certificate of all
deceased participants was obtained.
LABORATORY DATA. Blood samples were obtained
after an overnight fast for biochemical tests, which
were performed at the city hospital’s central labora-
tory using standard, quality-control procedures.
Glycated hemoglobin (HbA1c) was measured using
high-performance liquid chromatography. Serum
25-hydroxyvitamin D was measured by radioimmu-
noassay (RIA kit, DiaSorin, Stillwater, Minnesota).
The estimated glomerular filtration rate was calcu-
lated using the Modification of Diet in Renal Disease
formula. Total cholesterol, triglycerides, and high-
density lipoprotein cholesterol were calculated
using the enzymatic method. Low-density lipoprotein
cholesterol was calculated with the Friedewald
equation, unless triglycerides were higher than
400 mg/dl. The erythrocyte sedimentation rate was
measured using the Westergren method and sodium
citrate-anticoagulated blood samples.
STATISTICAL ANALYSIS. All measurements obtained
at baseline and follow-up were used in the data anal-
ysis. Participants’ characteristics were summarized
using mean  SD for continuous variables and counts
and percentages for categorical variables. For contin-
uous variables, normal distributions were tested using
the Shapiro-Wilk test. Age- and sex-adjusted p values
for trends were calculated as follows: for continuous
variables the differences between the means of the
covariates by number of frailty criteria were analyzed
using a general linear model; logistic regression was
applied for categorical variables.
The age-standardized incidence of CVD was
calculated as the number of new cases of CVD per
1,000 person-years during follow-up, standardized
according to the age structure of the Italian popula-
tion in 1991, and compared using logistic binary
regression. Cox proportional hazards models were
used to assess associations between participants
meeting 0, 1, or 2 frailty criteria and those with inci-
dent CVD. The time of first recorded event was
considered as the “time for event.” Known factors
associated with frailty and/or CVD were considered
JACC VOL. 65, NO. 10, 2015 Sergi et al. 979
MARCH 17, 2015:976–83 Pre-Frailty and CVD in the Elderly

for inclusion in the analysis. To explore whether a

T A B L E 1 Baseline Characteristics by Pre-Frailty Status (Fried Criteria) in the
variable should be included as a predictor in the final PRO.V.A. Study Sample (n ¼ 1,567)
survival model, the log-rank test of equality across
0 Criteria 1 Criterion 2 Criteria
strata was performed for all categorical variables, and (n ¼ 867) (n ¼ 491) (n ¼ 209) p Value*
Cox univariate proportional hazards regression for all Age, yrs 71.68  5.55 75.18  6.86 77.77  7.48 <0.0001†
continuous variables. The predictors included in the Female 53.4 66.2 77.5 <0.0001†
final model were all variables reaching a p < 0.20 in General characteristics
the univariate analyses (Online Table 1). Collinearity Current smokers 12.6 7.5 3.3 0.03

among covariates was quantified using the variance Previous smokers 31.8 24.2 18.2 0.69
Alcohol drinkers 76.6 67.6 65.1 0.007
inflation factor among the covariates. Waist circum-
GDS score 8.11  4.25 9.10  4.84 10.60  5.50 <0.0001
ference and BMI had a high collinearity (variance
MMSE score 25.76  3.78 23.87  5.07 23.04  4.96 <0.0001
inflation factor ¼ 4.58), but waist circumference was SBP, mm Hg 152.22  20.10 153.64  21.44 150.39  18.85 0.04
preferred because in older people it seems to be the DBP, mm Hg 84.00  10.31 83.68  11.14 81.71  11.44 0.29
best predictor of CVD onset (20). Hazard ratios (HRs) ABI 1.16  0.13 1.12  0.14 1.09  0.14 0.02
and 95% confidence intervals (CIs) were used to Anthropometric characteristics
compare CVD rates by number of frailty criteria taking BMI, kg/m2 27.38  4.13 27.93  4.44 28.44  5.18 <0.0001
Waist circumference, cm 95.51  10.71 95.64  11.21 97.40  14.46 <0.0001
those with 0 criteria for reference. HRs were also
Medical conditions and drugs
calculated for specific frailty criteria using the same
Atrial fibrillation 1.9 2.8 3.2 0.07
covariates as in the final model and taking for refer-
COPD 4.6 9.0 9.6 <0.0001
ence participants without a given condition. All ana- Hypertension 67.0 72.7 75.1 0.06
lyses were performed using SPSS 21.0 for Windows Diabetes 11.6 14.9 14.8 0.23
(SPSS Inc., Chicago, Illinois). All statistical tests were Use of antihypertensives 54.5 64.1 65.4 0.10
two-tailed and statistical significance was assumed Use of low-dose aspirin 5.2 10.8 6.8 0.37

for a p value <0.05. Use of anticoagulants 0.7 0.9 1.5 0.16

Use of lipid-lowering 4.1 2.4 1.5 0.08
drugs
RESULTS
Biohumoral tests
White blood cells, n/mm3 5.67  1.36 5.84  1.53 6.00  1.60 0.04
BASELINE CHARACTERISTICS. The sample consisted ESR, mm/h 16.17  16.40 20.14  17.01 24.77  18.55 0.005
of 1,567 elderly subjects (mean age 73.6  6.7 years; FPG, mmol/l 104.53  30.96 105.58  29.15 105.35  29.46 0.71
61% were women) with a mean BMI of 27.69  HbA1c, % 5.20  0.80 5.30  1.03 5.39  0.98 0.03
4.40 kg/m 2, with no CVD, frailty, or disability at 25OHD, nmol/l 93.41  55.04 81.15  50.08 75.35  57.22 <0.0001

baseline. Table 1 shows the baseline characteristics by eGFR, ml/min 72.44  16.26 71.48  18.53 67.66  21.51 0.01
Total cholesterol, mg/dl 235.87  42.20 230.68  42.55 231.05  43.81 0.07
pre-frailty criteria according to the number of frailty
HDL, mg/dl 58.14  17.04 61.74  33.09 61.75  64.46 0.04
criteria met. Pre-frail participants were older and
Triglycerides, mg/dl 133.56  73.24 129.31  70.82 140.58  85.60 0.21
more frequently women (p for trend <0.0001 for both LDL, mg/dl 153.00  36.56 147.43  37.39 149.98  39.29 0.004
variables). After adjusting for age and sex, the vari- Uric acid, mg/dl 5.07  1.29 5.18  1.47 5.19  1.73 0.04
ables of BMI, waist circumference, and GDS score
positively correlated with our modified Fried frailty Values are mean  SD or %. *Unless otherwise specified, p values are adjusted for age and sex using a general
linear model or logistic regression, as appropriate. †Not adjusted for age or sex, respectively.
score (Table 1). In contrast, current smoking and sys- 25OHD ¼ serum 25-hydroxyvitamin D; ABI ¼ ankle brachial index; BMI ¼ body mass index; COPD ¼ chronic
tolic BP were negatively associated with the modified obstructive pulmonary disease; DBP ¼ diastolic blood pressure; eGFR ¼ estimated glomerular filtration rate;
ESR ¼ erythrocyte sedimentation rate; FPG ¼ fasting plasma glucose; GDS ¼ Geriatric Depression Scale;
Fried frailty score (Table 1). No significant differences HbA1c ¼ glycosylated hemoglobin; HDL ¼ high-density lipoproteins; LDL ¼ low-density lipoproteins;
MMSE ¼ Mini-Mental State Examination; SBP ¼ systolic blood pressure.
in medical conditions were found across the groups,
with the exception of chronic obstructive pulmonary
disease, which was significantly higher in the pre-frail developed severe angina; 36 had acute MI, 249 had
participants (p for trend <0.0001). Compared with HF, and 8 had stroke; and 147 developed peripheral
nonfrail participants, those classified as pre-frail artery disease). As shown in Table 2, the age-adjusted
according to our modified Fried index had higher incidence of CVD in the sample as a whole was 75
white blood cell counts, erythrocyte sedimentation events per 1,000 person-years (95% CI: 64 to 86), with
rate, HbA 1c, uric acid, and high-density lipoprotein a significant trend for the incidence of CVD higher in
cholesterol levels, but lower ABI, low-density lipo- those meeting 2 frailty criteria (p for trend <0.0001).
protein cholesterol, 25-hydroxyvitamin D levels, and Compared with those who did not become frail,
estimated glomerular filtration rate (Table 1). participants meeting 1 criterion were at higher risk
FOLLOW-UP DATA. Over a period of 4.4 years, 551 CV of CVD (HR: 1.25; 95% CI: 1.05 to 1.64), whereas
events were recorded (84 participants died of CVD; 27 those meeting 2 criteria were at 80% higher risk of
980 Sergi et al. JACC VOL. 65, NO. 10, 2015

Pre-Frailty and CVD in the Elderly MARCH 17, 2015:976–83

T A B L E 2 Association Between Pre-Frailty Status* and CVD Risk

Standardized
Incidence Rate per 1,000
Person-Years Unadjusted
Number of Criteria (95% CI) Model p Value Model 1 p Value Model 2 p Value Model 3 p Value

0 68 (52–84) 1 [ref.] 1 [ref.] 1 [ref.] 1 [ref.]

1 77 (58–86) 1.51 (1.19–1.92) 0.001 1.23 (1.02–1.59) 0.03 1.18 (0.92–1.53) 0.09 1.25 (1.05–1.64) 0.03
2 99 (92–106) 2.20 (1.65–2.94) <0.0001 1.78 (1.28–2.40) <0.0001 1.64 (1.19–2.27) 0.003 1.79 (1.27–2.52) 0.001

Values are hazard ratio (95% CI) unless otherwise noted. *Pre-frailty status according to number of modified Fried criteria. Model 1: Adjusted for age and sex. Model 2: Adjusted for the covariates in Model 1
and presence of chronic obstructive pulmonary disease, alcohol drinking, serum 25-hydroxyvitamin D levels, and Geriatric Depression Scale score. Model 3: Adjusted for the covariates in the previous models
and waist circumference, presence of diabetes, hypertension, and atrial fibrillation; use of antihypertensive agents, low-dose aspirin, anticoagulant drugs, and statins; systolic blood pressure, diastolic blood
pressure, and ankle brachial index (as continuous variables); serum high-density lipoproteins, low-density lipoproteins, triglycerides, uric acid, fasting plasma glucose, glycosylated hemoglobin, erythrocyte
sedimentation rate, and white blood cells (as continuous variables); estimated glomerular filtration rate (as a continuous variable); and smoking status.
CI ¼ confidence interval; CVD ¼ cardiovascular disease.

experiencing a new CV event (HR: 1.79; 95% CI: 1.27 to
2.52) (Table 2). The higher risk of CV events during
follow-up was confirmed by the cumulative incidence
curve, adjusted for the same covariates as those used
in the final Cox model (Figure 1). The other covariates
significantly associated with the onset of new CV
events during follow-up were age (HR: 1.05; 95% CI:
1.03 to 1.07; p < 0.0001), GDS (HR: 1.02; 95% CI: 1.002
to 1.05; p ¼ 0.045), and atrial fibrillation (HR: 1.55;
95% CI: 1.03 to 2.91; p ¼ 0.03). The use of low-dose
aspirin was associated with a significant reduction
in the risk of new CV events (HR: 0.78; 95% CI: 0.52 to
0.96; p ¼ 0.03) (Online Table 2). As shown in Figure 2,
the frailty parameters proving the best predictors of
new CVD events were low energy expenditure (HR:
1.70; 95% CI: 1.07 to 3.50; p ¼ 0.03), exhaustion (HR:
1.53; 95% CI: 1.09 to 2.14; p ¼ 0.01), and slow gait
speed (HR: 1.28; 95% CI: 1.03 to 1.71; p ¼ 0.03),
whereas unintentional weight loss and weakness
were not associated with any significantly higher risk
of new cardiovascular events (p ¼ 0.51 and 0.19,
respectively).

DISCUSSION

F I G U R E 1 Cumulative Incidence of Cardiovascular Events

In our large cohort of community-dwelling elderly
men and women, pre-frailty significantly predicted
incident CVD. A 1-U increase in the modified Fried
score, signifying multisystem decline in physiological
60 2 criteria reserves and increased vulnerability to stressors, was
Cumulative Incidence (%)

associated with a 25% increased CVD risk. These

findings were consistent in both sexes and indepen-
1 criterion
40
dent of known clinical and metabolic risk factors. In
particular, pre-frailty was a significant predictor of
incident HF, and more than half of the CVD events
0 criteria
were HF-related. These findings are consistent with
20
data from several cross-sectional studies and one
longitudinal study showing that HF is the most
frequent type of CVD in frail and pre-frail elderly in-
0
dividuals (7,21,22).

0 1 2 3 4 5
The prevalence of pre-frailty in our cohort was
Years approximately 40% and, as expected, higher in
Number at risk
Modified Fried criteria women and older individuals (23,24). Given that this
0 867 846 790 731 701 637 population initially had no CVD or disabilities,
1 491 476 432 371 341 302
this prevalence is extremely high, underscoring the
2 209 191 162 123 104 85
potential importance of assessing pre-frailty in
apparently healthy elderly men and women. Pre-
The greater the number of Fried criteria, the higher the cumulative incidence of cardio-
vascular events over follow-up. The survival curves are based on adjusted Cox regression
frailty has been associated with a 4-fold higher risk
of cardiovascular events according to baseline number of Fried criteria, and the table to become frail over a 4-year follow-up (3), so it may
represents the number at risk of cardiovascular events according to baseline Fried criteria. be that this study’s worse outcomes were related to
pre-frail adults transitioning to frail phenotypes
JACC VOL. 65, NO. 10, 2015 Sergi et al. 981
MARCH 17, 2015:976–83 Pre-Frailty and CVD in the Elderly

transition from pre-frailty to frailty, and thereby

F I G U R E 2 Risk of Cardiovascular Events
contain the increase in CVD risk (Central Illustration)
(25–28).
Low Energy
Expenditure Pre-frailty and frailty have been described as bio-
logical syndromes resulting from the dysregulation of
Exhaustion
multiple metabolic pathways (1,11). Consistently, we
Slow Gait Speed found pre-frailty significantly associated with mea-

Weakness
Unintentional
Weight Loss
0 1 2 3
HR
Cardiovascular event risk varies by individual Fried criteria (and is
adjusted for the same covariates in Table 2). Unless otherwise
specified, data are presented as hazard ratios (HR) (squares) and
95% confidence interval (ticks).
during follow-up. It has been suggested that pre-
frailty is a reversible clinical condition if treated in
the early stages (3), meaning that such interventions
as cardiac rehabilitation, physical exercise, vitamin D
supplementation, and reducing unnecessary medi-
cation may be able to arrest frailty or delay the
sures of central adiposity, long-term glucose control,
and inflammation. The ABI was significantly lower in
pre-frail patients too, strongly suggesting early
atherosclerotic disease. Progressively adjusting for
4
these correlates did not attenuate the association
between pre-frailty and incident CVD, however,
implying that responsibility for the association
between pre-frailty and CVD lies in as-of-yet
unknown factors that need to be identified. Pre-
frailty may also represent the sum of several nega-
tive conditions and diseases that patients have
accumulated over a lifetime, making them more
sensitive to adverse health outcomes, including CVD.
Interestingly, the prevalence of clinical conditions,
such as depression, chronic obstructive pulmonary
disease, and hypovitaminosis D (thought to play an
independent role in the pathogenesis of CVD [29–31]),
was significantly higher in the participants who
became pre-frail. In particular, depression was an

CENTRAL I LLU ST RAT ION Possible Mechanisms and Interventions for Pre-Frailty as Cardiovascular Risk Factor
in the Elderly

Clinical condition predictors

MECHANISMS OF CVD

Depression; Inflammation; Comorbidities;

Central adiposity; Metabolic changes Atherosclerosis Increased risk
and/or of developing
cardiac function cardiovascular
impairment disease (CVD)
Pre-frailty criteria predictors
Slow gait speed (best predictor);
Exhaustion; Low energy expenditure

Multidimensional
INTERVENTIONS

assessment of Recommended interventions

elderly patient Cardiac rehabilitation
Identification of Physical exercise
1 or 2 pre-frailty Dietary assessment/vitamin D supplementation
criteria in
early stages Reduce unnecessary medication

Sergi, G. et al. J Am Coll Cardiol. 2015; 65(10):976–83.

Pre-frailty is associated with measures of central adiposity, long-term glucose control, and inflammation that could promote the onset of cardiovascular disease
(top). Multidimensional assessment is necessary to start beneficial interventions early that could slow the progression of cardiovascular disease (bottom).
982 Sergi et al. JACC VOL. 65, NO. 10, 2015

Pre-Frailty and CVD in the Elderly MARCH 17, 2015:976–83

important predictor of incident CVD in our sample,
probably because depression and frailty share the
same metabolic changes (i.e., more inflammation and
hypercortisolemia, and an increased adrenergic tone)
that have key roles in the pathogenesis of sarcopenia
and CVD (32). In our study, the risk of developing a
new CV event increased by 2% for each point on the
GDS, reinforcing the importance of diagnosing and
treating depression in elderly men and women at high
risk of CVD (33,34).
Another important finding of our study was the
relative importance of certain frailty criteria in pre-
dicting CVD events in pre-frail men and women. Low
energy expenditure, exhaustion, and slow gait speed
strongly predicted incident CVD, whereas uninten-
tional weight loss and handgrip strength did not. Our
data are consistent with other studies highlighting
the importance of walking speed as the best predictor
of frailty in patients with prevalent CVD (35). In
contrast with other studies on middle-aged adults
and disabled women (36,37), we failed to find any
significant association between handgrip strength
and the onset of new CVD. This would support the
CVD was carefully assessed by highly trained cardi-
ologists (even though no strict definitions of CVD and
HF were used). A second limitation of our study lies
in that weight loss was self-reported and physical
performance level was investigated using a non-
structural test. Finally, although the interviews were
conducted with the support of relatives, we cannot
exclude the presence of bias.
CONCLUSIONS
We demonstrated a significant association between
pre-frailty and the risk of incident CVD (irrespective
of any classical cardiometabolic risk factors). This
suggests that targeting pre-frailty as a potentially
reversible risk factor for CVD in the elderly could have
significant implications. Among the physical domains
of pre-frailty, low gait speed seems to be the single
best predictor of future CVD. More studies are war-
ranted to examine the effects of action to treat pre-
frailty or early stages of frailty for the purposes of
preventing CVD.
ACKNOWLEDGMENTS The authors acknowledge all

conviction that the prognostic importance of physical interviewers, nurses, and physicians who partici-
performance tests, and frailty criteria in general, pated in the study.
depends on the demographic characteristics of the
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
population under study and on the outcome being
Nicola Veronese, Department of Medicine–DIMED,
investigated. In our population, a low gait speed may
Geriatrics Division, University of Padua, Via Giustiniani,
be better able than a weak handgrip to reflect sys-
temic subclinical CV abnormalities and lesions, such 2 35128 Padua, Italy. E-mail: ilmannato@gmail.com.

as an abnormal ABI, left ventricular hypertrophy,

PERSPECTIVES
carotid intima-media thickening, and silent carotid
plaques (38,39). Consistent with this idea, it has been
reported that slow gait speed is a powerful predictor COMPETENCY IN PATIENT CARE: Screening
of hospitalization and post-operative morbidity and elderly people without overt disability for “pre-frailty”
mortality in patients with CVD (40,41). could identify individuals more likely to harbor car-
diovascular disease.
STUDY LIMITATIONS. First, because no imaging was
done to identify subclinical cardiovascular damage,
TRANSLATIONAL OUTLOOK: Clinical trials of in-
we cannot rule out the possibility of participants
terventions targeting the various domains of frailty
having a decline in heart function already at baseline.
are needed to ascertain whether treatment can pre-
It is well known that frail subjects could have an
vent clinical cardiovascular events.
underlying quiescent CVD, such as coronary artery
disease (42). In our sample, however, the presence of

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