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 communitydwelling, 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

independent predictor of disability, hospital and

of reduced physiological reserve and in-

nursing home admission, poor surgical outcomes,

creased vulnerability to poor resolution of ho-

and mortality (3–6). Data from observational studies

meostasis after a stressor event that occurs in 25% to

show a significant correlation between frailty and

50% of elderly patients with cardiovascular disease

CVD morbidity and mortality in the elderly (7–9),

(CVD) (1,2). The frailty phenotype is also a strong

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 Intramural 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.

Sergi et al.

JACC VOL. 65, NO. 10, 2015 MARCH 17, 2015:976–83

977

Pre-Frailty and CVD in the Elderly

found instrumental in refining their prognosis and

performance-based tests to document an

ABBREVIATIONS

defining optimal care and treatment for elderly indi-

extensive range of demographic, biological,

AND ACRONYMS

viduals (10).

and medical characteristics, with the support

ABI = ankle-brachial index

Several metabolic and hormonal factors, some of

of standardized algorithms (14). Cognitive

which have also been implicated in the pathogenesis of

function was assessed with the 30-item

CVD (e.g., chronic low-grade inflammation and insulin

Mini-Mental State Examination and depres-

resistance) (1,2), are responsible for the gradual bio-

sion with the Geriatric Depression Scale

CI = confidence interval

logical and functional decline that marks the transition

(GDS) (15,16). Face-to-face interviews and

CVD = cardiovascular disease

from a state of robustness to pre-frailty and, ulti-

clinical

mately, to frailty and its complications (11). It has been

trained physicians and nurses. The present

Depression Scale

hypothesized that the early detection of a pre-frail

study was approved by the Human Studies

HF = heart failure

status may provide a window of opportunity for more

Committee of Padua University and by

HR = hazard ratio

aggressive preventive or therapeutic interventions

the Veneto Region’s Local Health Units

MI = myocardial infarction

that might contain disability, hospitalization, and

No. 15 and No. 18. All subjects gave their informed

mortality (12,13). Few and contrasting data are avail-

consent.

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

assessments

were

performed

by

BMI = body mass index BP = blood pressure

GDS = Geriatric

MEASUREMENTS. Body weight was measured on a

calibrated balance scale. Height was determined using 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

The aim of this prospective study is to investigate

highest point of the iliac crest and the lowest part of

the impact of pre-frailty, defined using the 5 modified

the costal margin in the mid-axillary line. Body mass

Fried criteria (3) of: 1) unintentional weight loss; 2)

index (BMI) was calculated as: weight (in kilograms)/

low physical activity level; 3) weakness; 4) exhaus-

height (in meters) squared. Blood pressure (BP) was

tion; and 5) slow gait speed, on the risk of developing

measured

CVD in a cohort of community-dwelling elderly in-

(Erkameter 300, Erka, Bad Tölz, Germany) in both

dividuals with no disabilities, CVD, cancer, or de-

arms after the participant had been resting quietly for

mentia at baseline. We adopted a modified Fried scale

>5 min in a seated position. For the ankle-brachial

to ascertain pre-frailty because this is the most often

index (ABI) test, systolic BP was measured with BP

used frailty index (3) and it has consistently been

cuffs on the right brachial artery and both posterior

shown to predict disability and mortality in large co-

tibial arteries. ABI was calculated as the ratio of the

horts of elderly patients with and without CVD (4–9).

average ankle systolic to arm systolic BP, taking the

METHODS STUDY POPULATION. This study was based on an

with

a

mercury

sphygmomanometer

lowest value for reference; a value