JACC: ADVANCES VOL. -, NO.

-, 2025
ª 2025 THE AUTHORS. PUBLISHED BY ELSEVIER ON BEHALF OF THE AMERICAN

COLLEGE OF CARDIOLOGY FOUNDATION. THIS IS AN OPEN ACCESS ARTICLE UNDER

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VIEWPOINT

Prevent Frailty,
Prevent Cardiovascular Disease
Early Identification of Patients at Risk

Naila Ijaz, MD,a Michael G. Nanna, MD, MHS,b Abdulla A. Damluji, MD, PHD, MBAc,d

THE BI-DIRECTIONAL RELATIONSHIP FRAILTY AWARENESS AND DETECTION

BETWEEN FRAILTY AND CVD
In cardiovascular practice, patients frequently pre-
Frailty is a geriatric condition defined as an increased sent after they have developed CVD and are at risk for
vulnerability to internal and external stressors. The developing frailty or have already developed both.
most widely utilized instrument to diagnose physical Hence, knowledge of how to prevent frailty and
frailty is the Fried physical frailty phenotype, when at counseling patients on this subject is key to helping
least three of the five criteria are met: unintentional them maintain good cardiovascular health. Exercise,
weight loss, weakness, exhaustion, slowness, and low lipid management, blood pressure control, and dia-
physical activity. 1 There are other types of frailty that betes management have been associated with pre-
lead to vulnerability, including cognitive frailty, vention of physical frailty, just as they are associated
nutritional frailty, and psychosocial frailty. 1 Frailty with prevention of CVD. 2 The association between
prevention is highly relevant to the management of frailty and CVD has not only been proven by studies
cardiovascular disease (CVD) because it increases the on cardiovascular outcomes, but there is also evi-
risk of incident CVD, hospitalization, institutionali- dence that frailty is associated with cardiac structural
zation, and mortality. Additionally, it increases the changes that can be visualized on echocardiography
risk of periprocedural complications in patients with that predate clinical CVD and have been associated
CVD. CVD and frailty share risk factors and have with the development and progression of frailty. A
similar molecular underpinnings, including systemic recent study from the Atherosclerosis Risk in Com-
inflammation, metabolic dysfunction, and oxidative munities cohort demonstrated that the presence of a
stress.1 They also share a bidirectional relationship, greater left ventricular mass index, worse diastolic
with the development of one causing the other. function, and higher E/e’ ratio was associated with a
Frailty is reversible in its initial stages, hence it is greater likelihood of progressing to a worse frailty
important to identify and intervene. Interventions to status over a 5-year follow-up and similarly, frailty
reverse frailty are an area of ongoing research. was associated with similar echocardiographic
changes.3 This study showed a bidirectional associa-
tion between frailty and left ventricular remodeling
that predates heart failure with preserved ejection
fraction (HFpEF) among older adults and the re-
searchers proposed that interventions to modify one
From the aThomas Jefferson University Hospital, Philadelphia, Pennsyl- may exert beneficial effects on the other. Studies
vania, USA; bYale School of Medicine, New Haven, Connecticut, USA;
c
have also shown that patients with HFpEF are
Inova Center of Outcomes Research, Fairfax, Virginia, USA; and the
d
Johns Hopkins University School of Medicine, Baltimore, Maryland,
frequently affected by other comorbidities: chronic
USA. obstructive pulmonary disease, diabetes, anemia, and
The authors attest they are in compliance with human studies obesity.4 In many patients, these may be driving their
committees and animal welfare regulations of the authors’ institutions
frailty status. Hence, in frail and prefrail patients,
and Food and Drug Administration guidelines, including patient
consent where appropriate. For more information, visit the Author identifying the contributing factors, and intervening
Center. to treat physical frailty is essential to preventing CVD

ISSN 2772-963X https://doi.org/10.1016/j.jacadv.2025.101701

2 Ijaz et al JACC: ADVANCES, VOL. -, NO. -, 2025
Prevent Frailty, Prevent CVD - 2025:101701

ABBREVIATIONS (Figure 1). Interventions to address frailty

AND ACRONYMS may prevent or delay the development of KEY POINTS
clinical HFpEF and coronary artery disease.
CVD = cardiovascular disease
Frailty and CVD share a bidirectional
HFpEF = heart failure with relationship with similar underpinnings:
FRAILTY INTERVENTIONS AND
preserved ejection fraction inflammation and metabolic dysregulation.
BARRIERS TO CARE

Optimizing risk factors for CVD, that is,
obesity management, diabetes and blood
Of the many nutritional, pharmacological, and
pressure control, management of hyperlip-
exercise-based interventions studied to reverse
idemia, and identifying barriers to therapy,
frailty, it was found that exercise-based multimodal
including exercise, can prevent or reverse
rehabilitation interventions were the most promising
frailty in addition to delaying or preventing
in reversing frailty or preventing its progression.1
the onset of clinical CVD.
Exercise improves inflammation, decreases the risk

It is important to recognize frailty
of oxidative damage, improves mitochondrial func-
subtypes apart from physical frailty, that is,
tion, and improves insulin sensitivity.1 In these ways,
nutritional, psychosocial, and cognitive
it may prevent vascular changes that result in intima-
frailty, so that appropriate interventions
media thickening and increased arterial stiffness,
can be recommended.
which has been found to be associated with sarcope-

Older adults may find it more motivating to
nia. Exercise therapy has been proven to reverse
adhere to recommendations for CVD pre-
markers of frailty in patients with CVD, even those
vention when also put in context of pre-
recently admitted with HFpEF exacerbations.
venting physical frailty and functional
REHAB-HF (Rehabilitation Therapy in Older Acute
dependence.
Heart Failure Patients) showed improvement in
markers of physical frailty (short physical perfor-
mance battery, 6-minute walk distance, and frailty
interventions (whey protein supplementation) and
status as measured by modified Fried criteria) in pa-
cognitive training exercises have resulted in frailty
tients with acute decompensated heart failure who
reduction.1 Whereas not every intervention may be
were enrolled in an early, tailored, progressive
required for every patient, that is, patients with
physical rehabilitation program developed for frail
chronic kidney disease should not be on a high-
older adults with acute decompensated heart failure.5
protein diet, patients should be screened for risk fac-
However, older adults are frequently affected by
tors that put them at risk for these subtypes of frailty
conditions that prevent participation in exercise. In a
so that appropriate interventions can be identified.
systematic review of 25 qualitative studies assessing
Cognitive frailty also has similar underpinnings to
factors that influence physical activity in older adults,
physical frailty and CVD, hence addressing vascular
few factors that were found were slowness and fa-
risk factors can prevent or halt cognitive decline.7
tigue, alluding to the vicious cycle that frailty can put
individuals into, causing progressive frailty. 6 Addi- HFpEF AND OBESITY:
tional factors included arthritis, obesity, dizziness, AN UNDERRECOGNIZED SUBGROUP
drowsiness, environment, perception of capabilities, AT HIGH FRAILTY RISK
and fear of falls. Dizziness and drowsiness may be
due to polypharmacy, which is frequently overlooked A frequently underrecognized cohort at high risk for
in these patients. Not all adults may have access to a developing frailty and subsequent poor outcomes are
safe physical environment for exercise; hence, case patients with HFpEF and obesity. Frailty and HFpEF
managers should be engaged to identify community are closely related with 60% to 90% of patients with
resources. In those frail and prefrail patients with chronic stable HFpEF identifying as frail. 8 Obesity is a
CVD, cardiac rehabilitation should be offered and not major risk factor for younger-onset HFpEF. These
only include a supervised exercise intervention but patients are not typically identified as being at high
also help to identify and address barriers to exercise risk for frailty or being frail because they are not un-
in this population. derweight but are at high risk for developing limited
There is increasing recognition of the various sub- functional status and other sequelae from frailty.
types of frailty other than physical frailty, which Hence, interventions to modify risk factors and pre-
include nutritional frailty, psychosocial frailty, and vent or reverse HFpEF are essential for the preven-
cognitive frailty. Studies have shown that addition tion of frailty. There have been small advances in
of social support interventions and nutritional pharmacotherapy to improve functional status in
JACC: ADVANCES, VOL. -, NO. -, 2025 Ijaz et al 3
- 2025:101701 Prevent Frailty, Prevent CVD

F I G U R E 1 Early Interventions Can Prevent Progression of Frailty and Cardiovascular Disease

Frailty is associated with subclinical cardiovascular remodeling including left atrial dilation, greater left ventricular mass index, worse diastolic
function, and higher E/e’ ratio. Without appropriate interventions, these patients develop progressive frailty and cardiovascular disease,
including obstructive coronary artery disease, atrial fibrillation, and decompensated heart failure. Early interventions that include physical
exercise, identifying barriers to exercise, pharmacologic treatment of risk factors, that is, diabetes, hypertension, hyperlipidemia, and obesity,
and intervening with psychosocial, nutritional, and cognitive interventions, may reverse or halt the progression of frailty and prevent
cardiovascular disease. CVD ¼ cardiovascular disease; DM ¼ diabetes mellitus; HLD ¼ hyperlipidemia; HTN ¼ hypertension.

HFpEF patients, with the PRESERVED-HF (Effects of lower risk of primary composite outcome (major
Dapagliflozin on Biomarkers, Symptoms and Func- adverse heart failure outcomes, death from cardio-
tional Status in Patients with Preserved Ejection vascular causes, and worsening heart failure events)
Fraction Heart Failure) study showing use of dapa- but also demonstrated an improvement in health
gliflozain, a sodium-glucose transporter 2 inhibitor, is status, exercise tolerance, and a decrease in high-
associated with improvement in 6-minute walk dis- sensitivity C-reactive protein level, a marker of
tance.9 More recently, a glucagon-like peptide-1 re- systemic inflammation. It is important to note that
ceptor agonist has proven to improve cardiovascular the participants in this trial had an average age of
outcomes in patients with obesity and HFpEF. The 65 years and the oldest participants were 75 years of
SUMMIT (Tirzepatide for Heart Failure with Pre- age. Additionally, the reduction in inflammation as
served Ejection Fraction and Obesity) trial studied evident by biomarker analysis suggests improve-
tirzepatide treatment in patients with HFpEF and ment in the physiological processes that cause
obesity with a BMI $30 kg/m 2.10 Tirzepatide is a HFpEF, coronary artery disease, and frailty, making
glucagon-like peptide-1 agonist that has been proven this an important intervention for healthy cardio-
to be effective for weight loss. Results not only vascular aging and maintenance of functional
showed that patients treated with tirzepatide had a status.
4 Ijaz et al JACC: ADVANCES, VOL. -, NO. -, 2025
Prevent Frailty, Prevent CVD - 2025:101701

FUNCTIONAL INDEPENDENCE AS A Frailty that predates CVD may be caused by various

PREVENTATIVE HEALTH GOAL factors including obesity, arthritis that limits exercise
participation, drowsiness due to polypharmacy, and
Whereas it is important to counsel patients on unsafe environment for physical activity. These fac-
healthy behaviors to optimize their cardiovascular tors need to be identified and addressed early to help
health, that is exercise, lipid management, blood patients age gracefully by preventing frailty and CVD.
pressure management, diabetes management, it may ACKNOWLEDGMENT The authors thank Devon
be more motivating to adopt these behaviors when Stuart, MA, CMI, for her assistance with medical
patients are counseled that optimizing their vascular illustration.
health with these interventions will decrease their
risk of developing physical frailty. Whereas it may FUNDING SUPPORT AND AUTHOR DISCLOSURES
require some scientific knowledge to understand the
This work was supported by mentored patientoriented research
implications of CVD, it may be easier to comprehend career development award from the National Heart, Lung, and Blood
and more motivating to understand the concepts of Institute K23-HL153771. Dr Nanna has received unrelated current
maintaining functional independence and preventing research support from the American College of Cardiology Founda-
tion supported by the George F. and Ann Harris Bellows Foundation,
institutionalization. Hence, when older adults are
the Patient-Centered Outcomes Research Institute (PCORI), the
counseled on CVD prevention, frailty prevention Yale Claude D. Pepper Older Americans Independence Center
should also be a part of that discussion. (P30AG021342), and the National Institute on Aging (K76AG088428);
and has received personal fees from Heartflow, Inc, Merck, and Novo
CONCLUSIONS Nordisk. Dr Damluji has received research funding from the Pepper
Scholars Program of the Johns Hopkins University Claude D. Pepper
Older Americans Independence Center funded by the National Insti-
As the average life expectancy is increasing, the
tute on Aging P30-AG021334; mentored patient-oriented research
prevalence of geriatric syndromes is increasing,
career development award from the National Heart, Lung, and Blood
which make aging not only burdensome for older Institute K23-HL153771; the NIH National Institute of Aging R01-
adults but also their family members and adds sig- AG078153, and the Patient-Centered Outcomes Research Institute
(PCORI). Dr Ijaz has reported that she has no relationships relevant to
nificant financial implications on the health care
the contents of this paper to disclose.
system. Physical frailty leads to reduced patient in-
dependence, higher institutionalization rate, and
exacerbate chronic conditions including CVD, result- ADDRESS FOR CORRESPONDENCE: Dr Naila Ijaz,
ing in frequent hospitalizations. Therefore, early Division of Cardiology, Thomas Jefferson University
detection of frailty followed by interventions to pre- Hospital, 111 South 11th Street, Philadelphia, Penn-
vent or reverse frailty may positively influence the sylvania, USA. E-mail: [email protected].
incidence and progression of CVD in older patients. X handle: @NailaIjaz_MD.

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