Circulation: Heart Failure

ORIGINAL ARTICLE

A Randomized, Controlled Trial of Resistance

Training Added to Caloric Restriction Plus Aerobic
Exercise Training in Obese Heart Failure With
Preserved Ejection Fraction
Peter H. Brubaker , PhD; Barbara J. Nicklas, PhD; Denise K. Houston , PhD; W. Gregory Hundley, MD; Haiying Chen, PhD;
Anthony J.A. Molina , PhD; W. Mary Lyles , MD; Benjamin Nelson, MS; Bharathi Upadhya, MD; Russell Newland, BS;
Dalane W. Kitzman, MD

BACKGROUND: We have shown that combined caloric restriction (CR) and aerobic exercise training (AT) improve peak exercise
O2 consumption (VO2peak), and quality-of-life in older patients with obese heart failure with preserved ejection fraction.
However, ≈35% of weight lost during CR+AT was skeletal muscle mass. We examined whether addition of resistance
training (RT) to CR+AT would reduce skeletal muscle loss and further improve outcomes.

METHODS: This study is a randomized, controlled, single-blind, 20-week trial of RT+CR+AT versus CR+AT in 88 patients
with chronic heart failure with preserved ejection fraction and body mass index (BMI) ≥28 kg/m2. Outcomes at 20 weeks
included the primary outcome (VO2peak); MRI and dual X-ray absorptiometry; leg muscle strength and quality (leg strength ÷
leg skeletal muscle area); and Kansas City Cardiomyopathy Questionnaire.
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RESULTS: Seventy-seven participants completed the trial. RT+CR+AT and CR+AT produced nonsignificant differences
in weight loss: mean (95% CI): –8 (–9, –7) versus –9 (–11, –8; P=0.21). RT+CR+AT and CR+AT had non-significantly
differences in the reduction of body fat [–6.5 (–7.2, –5.8) versus –7.4 (–8.1, –6.7) kg] and skeletal muscle [–2.1 (–2.7,
–1.5) versus –2.1 (–2.7, –1.4) kg] (P=0.20 and 0.23, respectively). RT+CR+AT produced significantly greater increases
in leg muscle strength [4.9 (0.7, 9.0) versus –1.1 (–5.5, 3.2) Nm, P=0.05] and leg muscle quality [0.07 (0.03, 0.11)
versus 0.02 (–0.02, 0.06) Nm/cm2, P=0.04]. Both RT+CR+AT and CR+AT produced significant improvements in VO2peak
[108 (958, 157) versus 80 (30, 130) mL/min; P=0.001 and 0.002, respectively], and Kansas City Cardiomyopathy
Questionnaire score [17 (12, 22) versus 23 (17, 28); P=0.001 for both], with no significant between-group differences.
Both RT+CR+AT and CR+AT significantly reduced LV mass and arterial stiffness. There were no study-related serious
adverse events.

CONCLUSIONS: In older obese heart failure with preserved ejection fraction patients, CR+AT produces large improvements
in VO2peak and quality-of-life. Adding RT to CR+AT increased leg strength and muscle quality without attenuating skeletal
muscle loss or further increasing VO2peak or quality-of-life.
REGISTRATION: URL: https://ClincalTrials.gov; Unique identifier: NCT02636439.

Key Words: diastolic heart failure ◼ elderly ◼ exercise ◼ heart failure ◼ obesity ◼ resistance training

Correspondence to: Peter H. Brubaker, PhD, Department of Health and Exercise Science, Wake Forest University‚ Box 7868 Reynolda Station, Winston-Salem, NC
27109. Email brubaker@wfu.edu
This work was presented as an abstract at the American Heart Association Scientific Sessions, November 5–7, 2022, Chicago, IL.
Supplemental Material is available at https://www.ahajournals.org/doi/suppl/10.1161/CIRCHEARTFAILURE.122.010161.
For Sources of Funding and Disclosures, see page 125.
© 2022 American Heart Association, Inc.
Circulation: Heart Failure is available at www.ahajournals.org/journal/circheartfailure

Circ Heart Fail. 2023;16:e010161. DOI: 10.1161/CIRCHEARTFAILURE.122.010161 February 2023 116

 Brubaker et al
WHAT IS NEW?
• This is the first clinical trial to add resistance exer-
cise training (RT) to an already effective lifestyle
intervention of caloric restriction (CR) and aerobic
exercise training (AT), in older patients with obese
HFpEF. The addition of RT to CR+AT was well-tol-
erated and resulted in increased leg strength and
leg muscle quality without attenuating SM loss
or further increasing exercise capacity (VO2peak)
or QOL. These positive findings are particularly
notable in a study population, predominantly non-
White obese women, that is unduly burdened by
obese HFpEF and are often underrepresented in
clinical trials.
WHAT ARE THE CLINICAL IMPLICATIONS?
• The results of this study suggest that supervised
resistance training (RT), when added to caloric
restriction and aerobic exercise training (CR+AT),
appears to have no adverse effect on cardiac or
arterial structure and function, is safe, and was
not associated with any exercise-related adverse
events. Finally, improved LV mass, end-diastolic
volume, and arterial stiffness with CR and exercise
are highly relevant to HFpEF, where abnormalities
in each of these contribute to the pathogenesis and
severity of the disorder. Clinicians should consider
adding supervised RT to improve skeletal muscle
strength and muscle quality of older patients with
obese HFpEF.
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Nonstandard Abbreviations and Acronyms
AT aerobic exercise training
CR caloric restriction diet
HFpEF heart failure with preserved ejection
fraction
HFrEF HF with reduced ejection fraction
IMF intramuscular fat
LV left ventricle
QOL quality-of-life
RT resistance training
SM skeletal muscle mass
VO2peak peak exercise oxygen consumption
H
eart failure with preserved ejection fraction (HFpEF)
is the most common form of HF, particularly among
older persons and women, and is increasing in
prevalence1–4 Even when stable and well-compensated,
patients with chronic HFpEF have severe exercise
intolerance, with exertional dyspnea and fatigue, and
this is associated with severely reduced quality-of-life
(QOL).5–8 However, other than diet and exercise, there
Circ Heart Fail. 2023;16:e010161. DOI: 10.1161/CIRCHEARTFAILURE.122.010161
Resistance Training During CR+AT in HFpEF
are relatively few proven treatments for exercise intoler-
ance in HFpEF.9–12
Obesity is one of the strongest risk factors for HFpEF
2,5,13–15
and ≈85% of HFpEF patients are overweight/
obese, such that “obese/metabolic HFpEF” is the most
common HFpEF phenotype.5,11,16 compared with non-
obese HFpEF patients, those with the obese HFpEF
phenotype have worse symptoms, exercise capacity,
hemodynamic abnormalities, and QOL.17 We have shown
that patients with obese HFpEF have reduced skeletal
muscle mass and increased thigh muscle fat infiltration
and intra-abdominal fat mass, all of which are related to
their reduced exercise capacity.5,11,16–21
In a prior trial,11 we showed that in patients with obese
HFpEF, both caloric restriction (CR) and aerobic exercise
training (AT) significantly increased peak exercise oxy-
gen consumption (VO2peak), and their effects were addi-
tive. These data supported combined CR+AT as a novel
treatment to improve exercise intolerance and QOL in
older patients with obese HFpEF. However, ≈35% of
the weight lost (=2.5 kg) during CR was skeletal muscle
mass (SM), and this was not attenuated by the addition
of AT.11 The loss of SM is of concern because it may
attenuate gains in exercise capacity and has been asso-
ciated with increased risk of frailty, physical disability,
injuries, hospitalizations, and death.22–26 Thus, strategies
to further increase VO2peak during CR+AT by preserv-
ing skeletal muscle mass, strength, and muscle quality
in HFpEF warrant further investigation. Multiple lines of
evidence indicate that resistance training (RT) could be
an ideal addition to CR+AT for HFpEF.16–18,20–25 In HF
with reduced EF (HFrEF), RT improves VO2peak to a sim-
ilar degree as AT.26,27 In older adults and patients with
HFrEF, RT increases muscle mass, strength, and muscle
quality significantly more than AT.28,29 However, despite
these potential advantages, the addition of RT to AT, CR,
or their combination has not been formally evaluated
in patients with HFpEF. Furthermore, there have been
concerns that RT may have potential deleterious conse-
quences in HFpEF by further increasing blood pressure,
left ventricle (LV) hypertrophy and arterial stiffening.30
Thus, the purpose of this controlled, randomized, sin-
gle-blind trial was to determine whether adding RT to
CR+AT in obese older HFpEF patients further improves
VO2peak(primary outcome), and leg muscle mass, strength
and quality, QOL, and LV structure/function and arterial
function (secondary outcomes).
METHODS
The trial was conducted at Wake Forest University School
of Medicine from 2015 to 2021, institutional review board
approved, and registered (NCT02636439). Participants pro-
vided written informed consent. The data that support the find-
ings of this study are available from the corresponding author
upon reasonable request.
February 2023 117
 Brubaker et al
Study Participants
Potential participants were interviewed and examined by a
board-certified cardiologist who verified the diagnosis of HF
and participant qualification. As previously described and in
accord with the American College of Cardiology/American
Heart Association definition of HFpEF,2,8,10,11 key inclu-
sion criteria were: symptoms and signs of HF: LV EF ≥50%;
age ≥60 years; body mass index (BMI) ≥28 kg/m2; and either
NHANESHF (National Health and Nutrition Examination
Survey heart failure) score ≥331 or the criteria of Rich et al,32
or both. Major exclusion criteria were: prior history of reduced
LV EF (<45%); significant ischemic or valvular heart disease;
or any other disorder that could explain the participants’ symp-
toms. Participants were clinically stable and were not undergo-
ing regular exercise or diet programs prior to enrollment.
Outcomes
Primary Outcomes
Outcomes were assessed by personnel who were blinded
to participant group assignment at baseline and after the
20-week intervention. VO2peak (in mL/min) was determined by
expired gas analysis (Ultima, Medical Graphics) and obtained
during the last 30 seconds of exercise on a treadmill (Modified
Naughton Protocol) to exhaustion.11
Secondary Outcomes
Total body fat and lean mass were measured by using dual x-ray
absorptiometry (Hologic Inc).11 Scans of the thigh, abdomen, and
heart were performed by magnetic resonance imaging (MRI) as
previously described.11 Cross-sectional areas of SM, subcutane-
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ous fat, intramuscular fat (IMF), and bone were measured at the
mid-thigh of the left leg. Total thigh area was calculated as the
sum of subcutaneous fat, IMF, SM and bone, and thigh compart-
ment area was calculated as the sum of SM, IMF, and bone. A slice
at the second lumbar vertebra was used to determine abdominal
fat measurements, including subcutaneous fat, visceral and intra-
peritoneal and retroperitoneal fat. Epicardial and paracardial fat
volumes, were assessed by MRI, as previously described.11
Knee extensor strength (Nm) was assessed by isokinetic
dynamometry (Biodex Medical Systems Inc, Shirley, NY) at 60°
per second, with participant seated and hips and knees flexed at
90° as previously described.11,33 Participants performed 4 repeti-
tions; 2 trials on each leg. Peak torque (Nm) for the dominant leg
were used in analyses. SM quality was calculated as the ratio of
knee extensor strength to thigh muscle area assessed by MRI
(Nm/cm2).11,34 Six-minute walk distance was measured accord-
ing to the American Thoracic Society, and the Short Physical
Performance Battery was conducted as previously described.11,35
Heart failure–specific QOL was assessed with the Kansas City
Cardiomyopathy Questionnaire, and general QOL was assessed
with EuroQOL as well as the 36-item Short-Form Health Survey
physical component score.36 Doppler echocardiograms were per-
formed and analyzed per American Society of Echocardiography
recommendations. Carotid-femoral pulse-wave velocity was
assessed as previously described.11 LV mass and volumes were
assessed by cardiac MRI, as previously described.11
Randomization
After baseline testing, participants were randomly assigned to
either RT+CR+AT or CR+AT, stratified by sex.
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Resistance Training During CR+AT in HFpEF
Interventions
Caloric Restriction
Participants in both groups were prescribed a hypocaloric diet
using meals (lunch, dinner, and snacks) prepared by the Wake
Forest Clinical Research Unit Metabolic Kitchen under the
direction of a registered dietitian, as previously described and
as detailed in the Supplemental Material.11,37,38
Aerobic and Resistance Exercise Training
The exercise prescription was based on American College of
Sports Medicine and American Heart Association guidelines
for older persons and for HFrEF39,40 and were individualized
and progressive. Both groups exercised 3 times per week for
20 weeks. Warm-up and cool-down phases were ≈5 to 0 min-
utes of stretching, flexibility, and light walking. The total stimu-
lus phase of the RT+CR+AT was ≈60 minutes (40 minutes
for AT and 20 minutes for RT). To maintain a similar duration
between groups, for the CR+AT group, ≈20 minutes of light
chair-based range-of-motion, stretching, and flexibility exer-
cises were included at the end of the 40-minute aerobic exer-
cise sessions; this 20 minute added “control period” provided
no resistance or aerobic exercise. Sessions were conducted
with medical supervision to ensure safety and a uniform,
robust stimulus. To eliminate potential for cross-group con-
tamination, treatment groups exercised at different times.
The AT component was identical for both groups and
included walking on an indoor track and/or stationary cycling,
and was identical to that previously described11 and as detailed
in the Supplemental Methods.
The RT component (for the RT+CR+AT group only) was per-
formed immediately after the AT session with heart rate, blood
pressure, and cardiac rhythm monitored before and afterward.39,40
The RT program was designed to allow a gradual progression so
that participants could become familiar with the equipment, mini-
mize muscle soreness, and reduce potential for injury. In accor-
dance with published recommendations,39,40 and to optimize the RT
stimulus for maximal functional gains, the exercise prescription was
based on a relative intensity level and progressed at a rate specific
to the individual’s strength gains. The RT consisted of 2 upper body
(chest press and compound row) and 4 lower body (leg extension
and flexion, seated leg press, and calf plantar flexion) on Nautilus
RT equipment. For the initial 3 weeks, 1 set of 8 to 12 repetitions
was performed for each RT exercise which then progressed to 2
sets of each after 4 weeks. Using a 2:1 recovery- exercise ratio (1
minute of recovery after 30 seconds of RT), the RT (12 total sets of
RT exercises) required a total of ≈20 minutes. The initial resistance
setting on each piece of equipment began at 20–30% of partici-
pants’ 1 repetition maximum (1-RM) but increased to 40–50%
of 1-RM after 4 weeks. During the study, if >12 repetitions were
completed on the second set in 2 consecutive sessions, the resis-
tance for that exercise was increased by ≈5% for the next session.
The 1-RM testing was repeated every 4 weeks to assess gains in
strength and to ensure optimal resistance settings.
Statistical Analysis
This 2-arm, randomized, parallel design trial was designed to
test the effect of adding RT to a previously tested regimen of
CR+AT, using an intention-to-treat analysis, in older patients with
obese HFpEF. Analysis on the main outcome of absolute VO2peak
(mL/min) collected at week 20 was conducted using ANCOVA
February 2023 118
 Brubaker et al
with baseline measure, age, and sex as predefined covariates.
Similar analyses were performed for all secondary/exploratory
outcomes to evaluate treatment effect. A 2-sided P value of
0.05 was used to determine significance. To assess within-group
changes, we used constrained linear mixed-effects models
adjusted for age and sex. Baseline and 20-week measures were
analyzed together as a dependent variable. The models included
treatment, visit, and treatment-by-visit interaction under the con-
straint that the baseline measures are equal across treatment
arms to reflect the design of the randomized trial. Within-group
differences were estimated using linear contrasts.
Sample size calculations were based on data from our previ-
ous trial of CR+AT.11 The square root of the mean square error
from an ANCOVA model was estimated to be 107.5 mL/min. In
order to have 90% power to detect a relative effect due to RT
of 5.6% (absolute difference of 82.0 mL/min) in VO2peak at the
0.05 2-sided level of significance, the study required 38 evalu-
able participants per group. To allow for 15% loss to follow-up,
44 subjects per group (total: 88) were randomized. The sample
size also had power to test the secondary outcomes.
RESULTS
As shown in Figure 1, 424 participants were screened
by telephone, and 132 were scheduled for a screening
visit. Ultimately, 88 participants (mean±SD: age, 68±5
years; BMI, 40±6 kg/m2) were enrolled and random-
ized: RT+AT+RT (n=44) and CR+AT (n=44; Figure 1).
Of these, 77 participants (RT+CR+AT n=39; CR+AT
n=38) completed the intervention and had evaluable
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testing for the primary outcome (Figure 1). Two partici-
pants (both RT+CR+AT) were excluded from analysis of
the primary outcome: 1 because exercise effort judged
by the blinded tester was clearly submaximal, and 1 due
to malfunctioning expired gas collection. Exercise atten-
dance was 82±8%, and diet adherence was 99±1%.
There were no study-related serious adverse events.
Participant characteristics were in accord with those in
population-based HFpEF studies (Table 1).
Primary Outcome
VO2peak increased significantly in both the RT+CR+AT
and CR+AT groups (108 versus 80 mL/min, respec-
tively, which equates to 7% and 5% improvement from
baseline) with no significant between-group difference
(44 (–25, 112) mL/min; P=0.21). Effect sizes for the
primary (and key secondary outcomes) are presented in
Figure 2 (central figure).
Secondary Outcomes
Significant within-group improvements, without between-
group differences, were also observed for other expres-
sions of exercise capacity or physical function (VO2peak
mL/kg per minute, VO2peak mL/kg lean body mass per
minute, VO2peak mL/kg leg lean mass per minute, VO2peak
mL/cm2 thigh muscle per minute, exercise time, peak
Circ Heart Fail. 2023;16:e010161. DOI: 10.1161/CIRCHEARTFAILURE.122.010161
Resistance Training During CR+AT in HFpEF
workload, peak METs, and 6-minute walk distance and
Short Physical Performance Battery), as well as multiple
HF-specific and general QOL measures, NYHA class,
and depression scores (Table 2).
The total weight loss (Table 3) of –8 versus –9 kg (8%
versus 9%) was significant in both the RT+CR+AT and
CR+AT groups, respectively. Dual x-ray absorptiometry
revealed that both the RT+CR+AT and CR+AT groups
lost significant amounts of body fat (–6.5 versus –7.4
kg; a decrease of 12% versus 13%), percent body fat
(–2.2% versus –2.5%), and SM (–2.1 versus –2.1 kg),
respectively. However, the percentage of SM (relative to
total body weight) increased significantly in both groups
(2.0% versus 2.5%, respectively). There were no sig-
nificant between-group differences for these dual x-ray
absorptiometry derived body composition measurements.
Thigh MRI (Table 3) revealed that both groups sig-
nificantly decreased subcutaneous fat area (–23.5 ver-
sus –24.0 cm2; a decrease of 14% versus 13%), IMF
area (–3.6 versus –4.2 cm2; a decrease of 11% versus
12%), and SM area (–2.9 versus –3.0 cm2; a decrease
of 2% versus 2%), respectively. Consequently, thigh skel-
etal muscle SM:IMF ratio increased significantly in both
groups by 1%. There were no significant differences
between groups for changes in thigh tissue composition.
Abdominal MRI (Table 3) revealed that abdominal
subcutaneous fat visceral fat decreased significantly
within both groups, with no significant between-group
differences.
Despite decreased SM in both groups, leg muscle
strength improvement was observed in RT+CR+AT
(4.9 Nm [5.4%]) but not CR+AT (–1.1 Nm [–1%]) with
a between-group difference of 6.4 (–0.1, 12.9) Nm,
P=0.053. Also, muscle quality improved significantly in
the RT+CR+AT group (0.07 Nm/cm2=8.7%) but not in
CR+AT (0.02 Nm/cm2=–1%), with a between-group dif-
ference of 0.07 (0.00, 0.13) Nm/cm2, P=0.043.
Both RT+CR+AT and CR+AT significantly reduced LV
mass and arterial stiffness with no between-group differ-
ences (Table 3). Epicardial, pericardial, and paracardial fat
were all unchanged from baseline to follow-up (Table 3).
DISCUSSION
This study is the first to examine whether addition of RT
to CR+AT in older individuals with obese HFpEF further
improves exercise capacity and attenuates loss of SM
during CR+AT. In these older patients with obese HFpEF,
we achieved excellent adherence to both exercise and
dietary interventions and considerable weight reduction.
This was associated with clinically meaningful improve-
ments in both physical function and QOL, in accord with
our prior trial results.11 This trial significantly extends prior
knowledge by demonstrating that addition of RT appeared
safe, was well tolerated, and significantly improved leg
strength and muscle quality, without further increasing
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 Brubaker et al Resistance Training During CR+AT in HFpEF
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Figure 1. Flow of participants through the study.

AT indicates aerobic exercise training; BMI, body mass index; COPD, chronic obstructive pulmonary disease; CPET, cardiopulmonary
exercise testing; CR, caloric restriction; eGFR, estimated glomerular filtration rate; MRI, magnetic resonance imaging; NYHA, New York Heart
Association; and RT, resistance training.

VO2peak or attenuating SM loss. Both RT+CR+AT and
CR+AT significantly reduced LV mass and arterial stiff-
ness, potentially important outcomes in HFpEF.
Effect of Adding RT on Exercise Capacity and
QOL
VO2peak (mL/min) was the pre-planned primary outcome
as it assesses total oxygen utilization during maximal
exercise and is not directly influenced by changes in
bodyweight. Both had significant, clinically meaningful
increases in VO2peak, by 7% and 5%, respectively, without
significant between-group difference. When VO2peak was
expressed in mL/kg per minute, there were improve-
ments of 2.2 and 2.4 mL/kg per minute (15% and 16%),
in the RT+CR+AT and CR+AT groups, respectively. This
magnitude of improvement in indexed peak (mL/kg per
minute) VO2 is large, and substantially exceeds the clini-
cally meaningful differences of 1.0 mL/kg per minute
and 10% for this clinical population.41 However, contrary

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 Brubaker et al Resistance Training During CR+AT in HFpEF

Table 1. Baseline Characteristics of Treatment Groups at to our hypothesis, addition of RT to CR+AT did not result
Randomization in further increased VO2peak.
CR+AT RT+CR+AT P Other secondary measures of exercise performance,
Characteristic (n=44) (n=44) value including exercise time to exhaustion (2.3 versus 2.2
Age, y 67.9±5.4 69.7±5.8 0.13 minutes; 1 minute is clinically meaningful) and 6-minute
Women 37 (84%) 38 (86%) 0.76 walk distance (47 versus 61 meters; 30 meters is clini-
White 19 (46%) 21 (48%) 0.67 cally meaningful) also showed large, clinically meaning-
Weight, kg 106.1±19.6 104.3±17.9 0.57 ful, significant improvements in both groups, supporting
Body surface area, m2 2.08±0.22 2.07±0.20 0.80 improved exercise capacity. The Short Physical Perfor-
Body mass index, kg/m2 40.0±5.9 39.2±5.6 0.71 mance Battery also improved significantly by 0.8 units in
Body fat, % (by DXA) 50±4 49±4 0.33 both groups; clinically meaningful change is 0.6 units.35
Cardiovascular measures While both the disease-specific (Kansas City Cardio-
NYHA class
myopathy Questionnaire) and multiple general measures
  II 15 (34%) 16 (36%) 0.82
(36-item Short-Form Health Survey; EuroQOL) of QOL
improved significantly with CR+AT, the addition of RT did
  III 29 (66%) 28 (64%)
not produce further improvements in these measures.
Ejection fraction, % 61±5 61±6 0.63
The Kansas City Cardiomyopathy Questionnaire score at
Relative wall thickness 0.51±0.09 0.52±0.08 0.69
baseline (mean of 69) indicated moderately impaired QOL
Diastolic filling pattern*
yet both CR+AT and CR+AT+RT groups produced large
Normal 1 (2%) 3 (7%) 0.47
improvements of 15 to 20 points during the intervention,
Impaired relaxation 38 (86%) 37 (84%) greatly exceeding the threshold for clinically meaningful
Pseudonormal 5 (11%) 3 (7%) improvement of 5 points, confirming the strong effect of
Restrictive 0 (0%) 1 (2%) exercise plus dietary weight loss interventions in these
e′, cm/s 6.4±1.6 6.5±2.1 0.77 patients.11,42 NYHA class by a blinded observer improved
E/e′, ratio 13.3±6.4 13.1±4.5 0.89 as well. Depressive symptoms, measured by the CES-D
NT-proBNP, pg/mL, median 55 (42, 89) 100 (55, 154) 0.048 instrument, also significantly improved.
(IQR)†
Systolic blood pressure, mm Hg 137±14 135±15 0.59
Diastolic blood pressure, mm Hg 79±9 77±10 0.35
Effect of Adding RT on Body Weight/
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Comorbidities
Composition
History of atrial fibrillation 0 (0%) 4 (9%) 0.041 Both RT+CR+AT and CR+AT produced large, significant
Diabetes 14 (32%) 20 (45%) 0.19 reductions in body weight, body fat, subcutaneous and
Hypertension 42 (95%) 42 (95%) 1.00 visceral fat, and thigh IMF, with no between-group differ-
Current medications ences. By MRI, both groups had significant reductions,
ACE inhibitor 8 (18%) 12 (27%) 0.31
with no significant between-group difference in abdomi-
Angiotensin receptor blocker 20 (45%) 15 (35%) 0.31
nal subcutaneous (15% versus 14%) and visceral fat
Diuretic 36 (82%) 36 (84%) 0.81
(16% versus 18%), respectively. It is known that a reduc-
tion of 5% to 10% total bodyweight and/or body fat,
Beta-blocker 18 (41%) 17 (40%) 0.90
particularly abdominal visceral fat, has many favorable
Calcium antagonist 16 (36%) 19 (44%) 0.46
health benefits in clinical populations, including patients
Aldosterone antagonist 2 (5%) 5 (12%) 0.22
with diabetes and with HFpEF.11,43,44 Despite improved
Nitrate 2 (5%) 4 (9%) 0.38
exercise capacity and QOL, there was no significant
Insulin 4 (9%) 10 (23%) 0.07
change in epicardial or pericardial fat by MRI, a robust
Oral diabetic agents 11 (25%) 19 (44%) 0.06 technique for measuring this outcome.
Metformin 7 (16%) 13 (30%) 0.13 Most weight loss studies, including our prior trial of
Sulfonylureas 5 (11%) 6 (14%) 0.75 CR+AT in obese HFpEF, observed that 30% to 40% of
GLP-1 receptor agonist 0 (0%) 1 (2%) 0.31 the weight lost is lean body mass, which is primarily SM tis-
D-PP4 inhibitor 1 (2%) 2 (5%) 0.56 sue.43,45 Skeletal muscle loss is concerning as it may hinder
Antidepressant 15 (35%) 11 (26%) 0.35 further gains in exercise capacity, reduce basal metabolic
Data are presented as mean±SD or N (%), unless otherwise noted. ACE in- rate/caloric expenditure, and has been associated with dis-
dicates angiotensin-converting enzyme; AT, aerobic exercise training; D-PP4‚ di- ability, hospitalizations, and death.23,24,46 Despite providing
peptidyl peptidase-4; DXA, dual x-ray absorptiometry; E, E-wave velocity; e′, early a guideline-based RT program, and optimal protein intake
mitral annulus velocity (septal); GLP-1‚ glucagon-like peptide 1; IQR, interquartile
range; NT-proBNP‚ N-terminal pro-B-type natriuretic peptide; NYHA, New York (>1.2 g protein/kg body weight per day), the RT+CR+AT
Heart Association; and RT, resistance training. group had no significant difference in SM loss (–2.1 kg)
*Diastolic filling pattern determined according to American Society of Echo- and thigh skeletal muscle area loss (≈3 cm2) as the CR+AT
cardiography criteria.
†Sample size for NT-proBNP collection=27 (N=13 for CR+AT and N=14 for group. This outcome was contrary to our hypothesis, as
RT+CR+AT). prior studies have shown that RT, in the absence of caloric
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 Brubaker et al
Figure 2. Effect sizes for the primary (peak VO2) and key secondary outcomes (strength and body/muscle composition) from
baseline to 20-week follow-up.
AT indicates aerobic exercise training; CR‚ caloric restriction; RT‚ resistance training; and VO2peak m/min‚ peak exercise oxygen consumption.
restriction, increases muscle mass in older adults in gen-
eral and in patients with HFrEF.27,29 Moreover, RT has been
shown to attenuate SM loss during hypocaloric weight loss
in healthy adults.47 The mechanisms for the lack of attenu-
ation of SM loss in older patients with obesity and HFpEF,
despite the addition of RT, could be catabolism of low qual-
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ity SM, thereby preserving and enhancing quality of the
remaining muscle tissue.
Lower Extremity Muscle Mass, Strength, and
Quality
Although it has been postulated that reduced SM plays
a major role in the age-related decline of strength, initial
SM and changes SM explain only a small portion (≈5%)
of variability of age-related strength decline.48 In Health
ABC,49 the loss of SM was associated with the decline
in strength in older adults, but the decline in strength
was much more rapid than the concomitant loss of SM,
suggesting there is a decline in muscle quality during
aging. Moreover, maintaining or gaining muscle mass did
not seem to prevent aging-associated declines in mus-
cle strength in Health ABC participants.49 The present
investigation demonstrated, for the first time in this clini-
cal population, that the addition of RT to CR+AT resulted
in a significantly greater improvement in both isokinetic
lower extremity strength and skeletal muscle quality. Peak
torque during leg extension significantly increased by
16% (89.5–103.9 Nm) in the RT+CR+AT but decreased
by 8% (105.8 versus 97.5 Nm) in CR+AT group, indicat-
ing that addition of RT completely prevented this loss
and even improved muscle strength. Although several
studies have demonstrated the positive impact of RT on
Circ Heart Fail. 2023;16:e010161. DOI: 10.1161/CIRCHEARTFAILURE.122.010161
Resistance Training During CR+AT in HFpEF
muscle strength in weight stable patients with HFrEF,26–
30
this is the first study to demonstrate that RT can
produce improvement in lower limb muscular strength
during CR+AT induced weight loss in older patients with
obese HFpEF. These positive effects of adding RT may
be clinically important given the age of these patients,
the concomitant effect of aging, and the additional SM
loss due to the HFpEF condition which we previously
reported.16–18,23 Indeed, muscle strength is an important
clinical outcome among older persons, independent of
muscle mass; reduced skeletal muscle strength is strong
predictor of a range of adverse outcomes, including nurs-
ing home placement and death.
In addition to the well-recognized age and HF-related
reductions in SM quantity, there is substantial evidence
that SM quality may decrease as well.9,20,21,48 SM quality
is as the capacity to generate force relative to the mass/
volume of contractile tissue. Declines in SM strength with
aging are not completely explained by declines in muscle
mass.49,50 While strength alone quantifies the amount of
force a muscle can generate, larger muscles are not nec-
essarily stronger. A smaller muscle may be more effec-
tive at generating force, due to more contractile proteins,
less fat infiltration, or other physiological properties that
can alter the quality of the muscle.9,10,48,49 In the pres-
ent study, lower extremity (quadriceps) skeletal muscle
quality, assessed by the ratio of knee extensor strength
to thigh muscle area (expressed in Nm/cm2) as previ-
ously described,11 improved significantly in RT+CR+AT
(by 21%) but did not improve in the CR+AT group. Thus,
the current study indicates that during CR+AT induced
weight and fat loss, addition of RT can significantly
improve muscle quality in older patients with obese
February 2023 122
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Table 2. Exercise Performance and Quality of Life Outcomes by Treatment Group

CR+AT (n=38) RT+CR+AT (n=39) Treatment Effect Size

Within-group change Within-group change Between-group differ-

Brubaker et al

Exercise Performance Baseline Follow-up (95% CI) Baseline Follow-up (95% CI) ence (95%CI) P value
VO2peak, mL/min 1529±375 1609 (1561, 1657) 80 (30, 130)* 1530±366 1653 (1605, 1700) 108 (58, 157)† 44 (–25, 112) 0.21
VO2peak, mL/kg per minute 14.6±2.9 16.8 (16.3, 17.4) 2.2 (1.7, 2.7)† 14.8±2.9 17.1 (16.6, 17.6) 2.4 (1.9, 2.9)† 0.3 (–0.5, 1.0) 0.48
VO2peak, mL/kg lean body mass per 30.0±5.5 32.5 (31.5, 33.5) 2.9 (1.9, 3.8)† 29.7±5.1 33.3 (32.4, 34.3) 3.4 (2.5, 4.4)† 0.7 (–0.7, 2.1) 0.30
minute
VO2peak, mL/kg leg lean mass per minute 94.1±17.8 98.4 (96.7, 100.1) 4.9 (3.2, 6.6)† 92.6±18.0 98.8 (97.1, 100.4) 5.2 (3.5, 6.9)† 0.4 (–2.0, 2.8) 0.74
2
VO2peak, mL/cm thigh muscle per minute 14.1±2.9 15.0 (14.5, 15.5) 1.1 (0.6, 1.6)† 13.6±2.3 15.3 (14.8, 15.8) 1.3 (0.8, 1.8)† 0.3 (–0.4, 1.0) 0.40
Exercise time, min 9.2±2.4 11.3 (10.8, 11.8) 2.2 (1.7, 2.6)† 9.2±2.4 11.4 (10.9, 11.9) 2.3 (1.8, 2.6)† 0.1 (–0.6, 0.8) 0.83
METs 5.5±1.2 6.5 (6.2, 6.7) 1.1 (0.8, 1.3)† 5.4±1.2 6.6 (6.4, 6.8) 1.2 (1.0, 1.4)† 0.1 (–0.2, 0.5) 0.49
Peak heart rate, beats/min 142±21 136 (133, 140) –1 (–4, 3) 130±22 139 (136, 142) 3 (–1, 7) 2 (–2, 7) 0.32
Peak systolic blood pressure, mmHg 181±18 179 (173, 186) –6 (–12, 1) 187±21 177 (171, 183) –8 (–14, –1)* –2 (–11, 7) 0.63
Peak diastolic blood pressure, mmHg 81±10 72 (69, 75) –7 (–10, –4)† 77±30 73 (71, 76) –6 (–9, –3)† 1 (–3, 5) 0.54
Peak RER 1.08±0.10 1.11 (1.08, 1.14) 0.01 (–0.02, 0.05) 1.10±0.16 1.11 (1.08, 1.14) 0.02 (–0.02, 0.06) 0.00 (–0.04, 0.04) 0.94
VE/VCO2 slope 28.3±4.4 28.2 (27.4, 29.0) –0.9 (–1.7, –0.1)* 29.6±3.8 28.5 (27.8, 29.4) –0.4 (–1.2, 0.4) 0.3 (–0.8, 1.4) 0.62
6-minute walk distance, m 364±67 419 (405, 434)† 61 (47, 76) 353±74 405 (391, 419)† 47 (33, 60) –14 (–34, 6) 0.16
SPPB score 9.8±1.3 10.2 (9.8, 10.7)† 0.8 (0.3, 1.2) 9.1±2.0 10.2 (9.8, 10.6)† 0.8 (0.4, 1.3)† 0.0 (–0.6, 0.6) 0.99
Leg strength, Nm 105.8±29.8 97.5 (92.8, 102.1) –1.1 (–5.5, 3.2) 89.5±27.0 103.9 (99.5, 108.3)* 4.9 (0.7, 9.0)* 6.4 (–0.1, 12.9) 0.053
Leg muscle quality, Nm/cm2 0.96±0.18 0.90 (0.86, 0.95) 0.02 (–0.02, 0.06) 0.80±0.23 0.97 (0.93, 1.01)* 0.07 (0.03, 0.11)* 0.07 (0.00, 0.13) 0.043
Quality of Life
KCCQ score

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Overall 68±19 91 (88, 95) 23 (17, 28)† 70±19 87 (83, 90)† 17 (12, 22)† –5 (–10, 0) 0.07
Clinical 71±17 91 (87, 95) 20 (15, 25)† 71±19 86 (83, 90)† 15 (10, 20)† –5 (–10, 1) 0.09
Physical 72±19 91 (88, 96) 20 (14, 26)† 72±20 87 (83, 91)† 15 (9, 20)† –5 (–11, 1) 0.08
Social 70±26 95 (90, 100) 25 (17, 33)† 72±25 89 (84, 93)† 18 (11, 26)† –6 (–13, 0) 0.07
QOL 60±25 88 (84, 93) 26 (19, 33)† 65±25 84 (79, 88)† 20 (13, 27)† –5 (–11, 2) 0.16
Symptoms 70±19 90 (86, 95) 20 (14, 26)† 70±21 86 (82, 90)† 16 (10, 21)† –4 (–10, 2) 0.16
SF-36
Physical composite score 37±9 47 (45, 50) 10 (7, 13)† 38±9 47 (44, 50)† 9 (7, 12)† –1 (–4, 3) 0.79
Mental composite score 53±9 57 (55, 60) 4 (1, 7)* 53±12 57 (55, 59)* 3 (0, 6)* 0 (–4, 3) 0.95
EuroQol thermometer 72±15 84 (80, 88) 14 (9, 18)† 70±17 82 (78, 85)† 11 (7, 16)† –2 (–7, 3) 0.42
CES-D score 10±6 6 (5, 8) –3 (–5, –1)* 9±7 7 (5, 9)* –2 (–4, –0)* 1 (–2, 3) 0.66
NYHA class 2.7±0.5 1.7 (1.6, 1.9) –1.0 (–1.1, –0.8)† 2.6±0.5 1.8 (1.6, 1.9)† –0.9 (–1.0, –0.7)† 0.1 (–0.1, 0.3) 0.53

February 2023
Baseline data are presented as mean±SD. Follow-up data are presented as least-squares means (95% CI) adjusted for baseline value, age, and sex from ANCOVA. Within-group change estimates derived from constrained linear mixed-
effect models. CES-D indicates Centers for Epidemiologic Studies Depression Scale; KCCQ, Kansas City Cardiomyopathy Questionnaire; MET, metabolic equivalent; NYHA, New York Heart Association; QOL, quality of life; RER, respiratory
exchange ratio; SF-36, Short Form 36-item Health Survey; SPPB, Short Physical Performance Battery; VAT, ventilatory anaerobic threshold; VE/VCO2, ventilatory equivalent for carbon dioxide; and VO2, volume of oxygen consumption.
Resistance Training During CR+AT in HFpEF

123
*Significant at P<0.05.
†Significant at P<0.001.
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Table 3. Body Composition and Cardiac Function Outcomes by Treatment Group

CR+AT (n=38) RT+CR+AT (n=39) Treatment effect size

Within-group change Within-group change Between-group
Body composition Baseline Follow-up (95% CI) Baseline Follow-up (95% CI) difference (95% CI) P value
Brubaker et al

Weight, kg 106±20 96 (95, 97) –9 (–11, –8)*,* 104±18 97 (96, 98) –8 (–9, –7)† 1 (–1, 3) 0.21
DXA measurements
Skeletal muscle, kg 51.6±10.8 49.4 (48.8, 50.1) –2.1 (–2.7, –1.4)† 51.8±9.5 49.4 (48.8, 50.0) –2.1 (–2.7, –1.5)† –0.1 (–1.0, 0.8) 0.86
Fat, kg 53.0±10.5 45.2 (44.3, 46.0) –7.4 (–8.1, –6.7)† 51.3±10.6 46.0 (45.1, 46.8) –6.5 (–7.2, –5.8)† 0.8 (–0.4, 2.0) 0.20
Skeletal muscle, % 48.2±4.0 51.0 (50.6, 51.4) 2.3 (1.8, 2.7)† 49.2±4.2 50.6 (50.2, 51.1) 2.0 (1.6, 2.5)† –0.4 (–1.0, 0.2) 0.23
Fat, % 49.6±4.1 46.5 (46.1, 47.0) –2.5 (–3.0, –2.1)† 48.6±4.5 46.9 (46.5, 47.4) –2.2 (–2.7, –1.8)† 0.4 (–0.2, 1.1) 0.19
MRI measurements
Thigh
   Subcutaneous fat, cm2 181±64 141 (136, 145) –24 (–29, –19)† 162±71 141 (136, 145) –24 (–29, –18)† 0.2 (–6.2, 6.6) 0.95
   Skeletal muscle, cm2 111±30 109 (106, 111) –3 (–5, –1)* 113±21 109 (107, 111) –3 (–5, –1)* 0.5 (–2.8, 3.8) 0.77
   Intramuscular fat, cm2 34±11 29 (28, 30) –4 (–5, –3)† 32±10 30 (29, 31) –4 (–5, –3)† 0.3 (–1.1, 1.9) 0.66
  SM:IMF ratio 3.5±1.1 4.0 (3.8, 4.2) 0.4 (0.2, 0.6)† 3.7±1.1 4.0 (3.8, 4.1) 0.4 (0.2, 0.5)† 0 (–0.3, 0.2) 0.85
Abdominal
   Subcutaneous fat, cm2 375±121 326 (315, 338) –58 (–71, –45)† 400±110 329 (319, 340) –57 (–6, –45)† 3 (–13, 19) 0.72
   Visceral fat, cm2 194±106 165 (156, 174) –36 (–48, –25)† 194±89 172 (163, 180) –30 (–40, –20)† 6 (–6, 19) 0.29
Epicardial fat, cm2 24.1±13.2 25.9 (22.9, 28.9) 0.5 (–2.6, 3.6) 25.3±9.8 25.0 (22.5, 27.5) –0.5 (–3.2, 2.2) –0.9 (–4.9, 3.0) 0.64
Paracardial fat, cm2 24.0±13.8 24.9 (21.8, 27.9) –0.1 (–3.5, 3.3) 24.6±12.9 23.6 (21.1, 26.2) –1.0 (–3.9, 1.9) –1.2 (–5.2, 2.8) 0.55
Pericardial fat, cm2 48.1±26.4 50.8 (45.5, 56.0) 0.2 (–5.4, 5.9) 49.9±21.4 48.6 (44.2, 53.1) –1.8 (–9.1, 5.5) –2.1 (–9.0, 4.8) 0.54
Cardiac function
MRI measurements

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LV mass, g 101±20 100 (98, 103) –3 (–5, –1)* 107±21 102 (100, 104) –1 (–3, 1) 1 (–2, 5) 0.37
End-diastolic volume, mL 126±25 123 (119, 127) –5 (–9, 0)* 135±26 123 (120, 127) –5 (–9—, 1)* 0 (–5, 6) 0.89
LV mass/end-diastolic volume 0.81±0.13 0.82 (0.79, 0.85) 0.00 (–0.03, 0.03) 0.80±0.13 0.83 (0.80, 0.86) 0.02 (–0.01, 0.05) 0.01 (–0.03, 0.05) 0.49
Ejection fraction, % 61±5 61 (60, 62) 0 (–1, 1) 61±6 60 (59, 61) –1 (–2, 0) –1 (–2, 1) 0.36
Echo-Doppler measurements
LV mass, g 204±50 190 (179, 200) –14 (–25, –3)* 202±47 191 (181, 202) –11 (–22, –1)* 2 (–13, 17) 0.82
Relative wall thickness 0.51±0.09 0.53 (0.50, 0.55) 0.02 (–0.01, 0.04) 0.52±0.08 0.52 (0.50, 0.55) 0.00 (–0.02, 0.03) –0.01 (–0.04, 0.03) 0.66
Left atrium diameter, cm 3.9±0.6 4.0 (3.8, 4.1) 0.1 (–0.0, 0.2) 3.9±0.6 3.9 (3.8, 4.0) 0.0 (–0.1, 0.1) –0.1 (–0.2, 0.1) 0.28
E/A ratio 0.89±0.32 0.92 (0.86, 0.99) 0.06 (–0.00, 0.13) 0.87±0.27 0.91 (0.85, 0.98) 0.04 (–0.03, 0.10) –0.01 (–0.10, 0.08) 0.83
e′, cm/s 6.4±1.6 6.3 (5.9, 6.6) –0.1 (–0.6, 0.3) 6.5±2.1 6.1 (5.7, 6.4) –0.4 (–0.9, 0.0) –0.2 (–0.7, 0.3) 0.42
E/e′ ratio 13.3±6.4 13.6 (12.5, 14.6) 0.4 (–0.8, 1.6) 13.1±4.5 14.1 (13.1, 15.2) 1.2 (0.0, 2.3)* 0.6 (–0.9, 2.1) 0.42
Pulse wave velocity, cm/s‡ 1011±256 965 (909, 1020) –72 (–144, 0) 1057±352 959 (907, 1011) –84 (–152, –16)* –6 (–83, 71) 0.88

Baseline data are presented as mean±SD. Follow-up data are presented as least-squares means±SE (95% CI) adjusted for baseline value, age, and sex from ANCOVA. Within-group change estimates derived from constrained
linear mixed-effects models. AT indicates aerobic exercise training; CR, caloric restriction; DXA, dual X-ray absorptiometry; IMF, intramuscular fat; LV, left ventricular; e', early mitral annulus velocity (septal); E, E-wave velocity; E/A,
early to atrial filling velocity; MRI, magnetic resonance imaging; RT, resistance training; and SM, skeletal muscle.

February 2023
*Significant at P<0.05.
†Significant at P<0.001.

124
Resistance Training During CR+AT in HFpEF

‡Determined using carotid-femoral artery by Doppler echocardiography.

 Brubaker et al
HFpEF. Although the clinical importance of muscle qual-
ity is less established than muscle strength and mass,
because it takes into account both strength and body
composition, muscle quality is a highly relevant outcome
in older persons.23,43
Impact of RT on Cardiac Structure and Function
and Arterial Stiffness
CT+AT resulted in small but significant decreases in LV
and end-diastolic volume as well as a nearly significant
(P=0.06) increase in LV E/A ratio consistent, with our
previous findings.11 Addition of RT resulted in significant
improvements with no significant between-group dif-
ference in LV mass (by echo) and end-diastolic volume
(by MRI). Despite limited evidence, there are lingering
concerns that RT may negatively impact LV systolic and/
or diastolic function in HF patients via increased blood
pressure and LV afterload. While several studies have
examined the effect of RT in HFrEF,26–29 this is the first
trial to formally test the effects of adding RT to tradi-
tional AT in HFpEF. A novel finding was the favorable
effects on arterial stiffness, measured by carotid-femoral
pulse-wave velocity on Doppler echocardiography, which
were observed in both groups. This suggests that the
concern that RT may adversely HFpEF by increased
afterload may be unfounded. These results suggest that
supervised RT, when added to CR+AT, appears to have
no adverse effect on cardiac or arterial structure and
Downloaded from http://ahajournals.org by on June 7, 2024
function, is safe, and was not associated with any exer-
cise-related adverse events. Finally, improved LV mass,
end-diastolic volume, and arterial stiffness with CR and
exercise are highly relevant to HFpEF where abnormali-
ties in each of these contribute to the pathogenesis and
severity of the disorder.
Strengths and Limitations
Strengths of the current study include that it was a ran-
domized, controlled, single-blind clinical trial with a well-
defined population of older patients with obese HFpEF,
extensive phenotyping including with serial cardiopulmo-
nary exercise test and MRI, professionally administered CR
diet, and medically supervised AT and RT with careful and
frequent monitoring. Thus, efficacy and safety could differ
under other conditions. We did not test effects of RT alone,
without concomitant CR+AT. The minimum BMI for study
participants was 28, which is based on World Health Orga-
nization recommendations for dietary intervention for the
general population, and which includes most patients with
HFpEF. However, our data do not address safety and effi-
cacy of this intervention in patients with lower BMIs. The
participants had typical clinical features of obese HFpEF,
including severe exercise intolerance, LV hypertrophy, and
LV diastolic dysfunction, 93% were on maintenance diuret-
ics, and met predetermined criteria for HFpEF utilized in
Circ Heart Fail. 2023;16:e010161. DOI: 10.1161/CIRCHEARTFAILURE.122.010161
Resistance Training During CR+AT in HFpEF
prior publications2,8,10.11,31,32 and in accord with 2013 rec-
ommendations of the American Heart Association and
American College of Cardiology which were the most cur-
rent at the time of trial design. Patients enrolled in the study
were medically stable and well-compensated; therefore,
the results may not apply to other populations, particularly
those who are unstable or have acute decompensated
HFpEF, who may require other approaches.50 Although the
RT intervention was in accord with American College of
Sports Medicine guidelines for RT at the time, we cannot
exclude the possibility that increased stimulus (time and/or
intensity) and larger sample size could have produced sig-
nificantly increased muscle mass. However, SM strength
and muscle quality did improve significantly with RT, and
these outcomes are important to patients. Finally, we can-
not exclude that greater intensity of protein supplementa-
tion or RT may have reduced SM loss.
Conclusions
In older patients with obese HFpEF, combined CR+AT
produced robust weight loss and improvements in physi-
cal function (including the primary outcome of VO2peak),
QOL, body composition, as well as cardiac and arterial
function. The addition of RT to CR+AT was well-tolerated
and resulted in increased leg strength and leg muscle
quality without attenuating SM loss or further increasing
VO2peak or QOL. These positive findings are particularly
notable in a study population, predominantly non-White
obese women, that is unduly burdened by obese HFpEF
and are often under-represented in clinical trials.
ARTICLE INFORMATION
Received September 7, 2022; accepted October 6, 2022.
Affiliations
Department of Health and Exercise Science, Wake Forest University, Winston-
Salem, NC (P.H.B.). Section on Gerontology and Geriatric Medicine, Department
of Internal Medicine (B.J.N., D.K.H., W.M.L., D.W.K.), Department of Biostatistical
Sciences, Division of Public Health Sciences (H.C.), and Section on Cardiology,
Department of Internal Medicine (B.N., B.U., R.N., D.W.K.), Wake Forest University
School of Medicine, Winston-Salem, NC. Division of Cardiology, Department of
Internal Medicine, Virginia Commonwealth University, Richmond (W.G.H.). Depart-
ment of Medicine, Division of Geriatrics, Gerontology and Palliative Care, Univer-
sity of California San Diego, La Jolla (A.J.A.M.).
Sources of Funding
This study was supported by the National Institutes of Health (R01AG045551;
R01AG18915; P30AG021332; U24AG059624; U01 AG076928; U01HL160272)
and in part by the Kermit Glenn Phillips II Chair in Cardiovascular Medicine and by the
Oristano Family Fund at Wake Forest School of Medicine.
Disclosures
Dr Brubaker has received honoraria as a consultant for Boston Scientific, Boeh-
ringer Ingelheim, Corvia Medical, and Merck. Dr Kitzman has received honoraria
as a consultant for Bayer, Medtronic, Relypsa, Merck, Corvia Medical, Boehringer
Ingelheim, Ketyo, Rivus, NovoNordisk, AstraZeneca‚ and Novartis, grant funding
from Novartis, Bayer, NovoNordisk‚ and AstraZeneca‚ and has stock ownership
in Gilead Sciences.
Supplemental Material
Supplemental Methods
February 2023 125
 Brubaker et al
REFERENCES
1. Tsao CW, Aday AW, Almarzooq ZI, Alonso A, Beaton AZ, Bittencourt MS,
Boehme AK, Buxton AE, Carson AP, Commodore-Mensah Y, et al. heart
disease and stroke statistics—2022 update: a report from the Ameri-
can Heart Association. Circulation. 2022;145:e153–e639. doi: 10.1161/
CIR.0000000000001052
2. Yancy CW, Jessup M, Bozkurt B, et al. 2013 ACCF/AHA guideline for the
management of heart failure. J Am Coll Cardiol. 2013;62:e147–e239. doi:
10.1016/j.jacc.2013.05.019
3. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM.
Trends in prevalence and outcome of heart failure with preserved ejection
fraction. N Engl J Med. 2006;355:251–259. doi: 10.1056/NEJMoa052256
4. Kitzman DW, Gardin JM, Gottdiener JS, Arnold A, Boineau R,
Aurigemma G, Marino EK, Lyles M, Cushman M, Enright PL, Cardiovas-
cular Health Study Research Group. Importance of heart failure with pre-
served systolic function in patients > or = 65 years of age. CHS Research
Group. Cardiovascular health study. Am J Cardiol. 2001;87:413–419. doi:
10.1016/s0002-9149(00)01393-x
5. Pandey A, Shah SJ, Butler J, Kellogg DL, Lewis GD, Forman DE, Mentz RJ,
Borlaug BA, Simon MA, Chirinos JA, et al. Exercise intolerance in older adults
with heart failure with preserved ejection fraction: JACC state-of-the-art review.
J Am Coll Cardiol. 2021;78:1166–1187. doi: 10.1016/j.jacc.2021.07.014
6. Spertus JV, Hatfield LA, Cohen DJ, Arnold SV, Ho M, Jones PG,
Leon M, Zuckerman B, Spertus JA. Integrating quality of life and survival
outcomes cardiovascular clinical trials. Circ Cardiovasc Qual Outcomes.
2019;12:e005420. doi: 10.1161/CIRCOUTCOMES.118.005420
7. Kitzman DW, Little WC, Brubaker PH, Anderson RT, Hundley WG,
Marburger CT, Brosnihan B, Morgan TM, Stewart KP. Pathophysiological char-
acterization of isolated diastolic heart failure in comparison to systolic heart
failure. JAMA. 2002;288:2144–2150. doi: 10.1001/jama.288.17.2144
8. German CA, Brubaker PH, Nelson MB, Fanning J, Ye F, Kitzman
DW. Relationships between objectively measured physical activity, exer-
cise capacity, and quality of life in older patients with obese heart fail-
ure and preserved ejection Fraction. J Card Fail. 2021;27:635–641. doi:
10.1016/j.cardfail.2020.12.025
9. Lavie CJ, Carbone S, Neelan IJ. Prevention and treatment of heart failure.
Downloaded from http://ahajournals.org by on June 7, 2024
JACC Cardiovasc Imaging 2021;14:216–218. doi: 10.1016/j.jcmg.2020.
08.004
10. Upadhya B, Haykowsky MJ, Kitzman DW. Therapy for heart failure with pre-
served ejection fraction: current status, unique challenges, and future direc-
tions. Heart Fail Rev. 2018;23:609–629. doi: 10.1007/s10741-018-9714-z
11. Kitzman DW, Brubaker PH, Morgan T, Haykowsky M, Hundley G, Kraus
WE, Eggebeen J, Nicklas BJ. Effects of caloric restriction and aerobic exercise
training on peak oxygen consumption and quality of life obese older patients
with heart failure patients and a preserved ejection fraction: a randomized clini-
cal trial. JAMA. 2016;315(1):36–46. doi: 10.1001/jama.2015.17346
12. Nassif ME, Windsor SL, Borlaug BA, Kitzman DW, Shah SJ, Tang F,
Khariton Y, Malik AO, Khumri T, Umpierrez G, et al. The SGLT2 inhibitor
dapagliflozin in heart failure with preserved ejection fraction: a multi-
center randomized trial. Nat Med. 2021;27:1954–1960. doi: 10.1038/
s41591-021-01536-x
13. Nicklas BJ, Cesari M, Penninx BW, Kritchevsky SB, Ding J, Newman A,
Kitzman DW, Kanaya AM, Pahor M, Harris TB. Abdominal obesity is an inde-
pendent risk factor for chronic heart failure in older people. J Am Geriatr
Soc. 2006;54:413–420. doi: 10.1111/j.1532-5415.2005.00624.x
14. Haass M, Kitzman DW, Anand IS, Miller A, Zile MR, Massie BM, Carson PE.
Body mass index and adverse cardiovascular outcomes in heart failure
patients with preserved ejection fraction/ clinical perspective. Circ Heart
Fail. 2011;4:324–331. doi: 10.1161/CIRCHEARTFAILURE.110.959890
15. Carbone S, Canada JM, Buckley LF, Trankle CR, Dixon DL, Buzzetti R,
Arena R, Van Tassell BW, Abbate A. Obesity contributes to exercise intol-
erance in heart failure with preserved ejection fraction. J Am Coll Cardiol.
2016;68:2487–2488. doi: 10.1016/j.jacc.2016.08.072
16. Reddy YNV, Rikhi A, Obokata M, Shah SJ, Lewis GD, AbouEzzedine OF,
Dunlay S, McNulty S, Chakraborty H, Stevenson LW, et al. Quality of life
in heart failure with preserved ejection fraction: importance of obesity,
functional capacity, and physical inactivity. Eur J Heart Fail. 2020;22:1009–
1018. doi: 10.1002/ejhf.1788
17. Obokata M, Reddy YNV, Pislaru SV, Melenovsky V, Borlaug BA. Evidence
Supporting the Existence of a Distinct Obese Phenotype of Heart Fail-
ure With Preserved Ejection Fraction. Circulation. 2017;136:6–19. doi:
10.1161/CIRCULATIONAHA.116.026807
Circ Heart Fail. 2023;16:e010161. DOI: 10.1161/CIRCHEARTFAILURE.122.010161
Resistance Training During CR+AT in HFpEF
18. Kitzman DW, Nicklas B, Kraus WE, Lyles MF, Eggebeen J, Morgan
TM, Haykowsky M. Skeletal muscle abnormalities and exercise intoler-
ance in older patients with heart failure and preserved ejection frac-
tion. Am J Physiol Heart Circ Physiol. 2014;306:H1364–H1370. doi:
10.1152/ajpheart.00004.2014
19. Haykowsky M, Brubaker P, Morgan T, Kritchevsky S, Eggebeen J, Kitzman D.
Impaired aerobic capacity and physical functional performance in older heart
failure patients with preserved ejection fraction: role of lean body mass. J
Gerontol A Biol Sci. 2013;68:968–975. doi: 10.1093/gerona/glt011
20. Haykowsky M, Kouba EJ, Brubaker PH, Nicklas BJ, Eggebeen J,
Kitzman DW. Skeletal muscle composition and its relation to exercise intol-
erance in older patients with heart failure and preserved ejection fraction.
Am J Cardiol. 2014;113:1211–1216. doi: 10.1016/j.amjcard.2013.12.031
21. Carbone S, Kirkman DL, Garten RS, Rodriguez-Miguelez P, Artero EG,
Lee D-C, Lavie CJ. Muscular strength and cardiovascular disease: an updated
state-of-the art narrative review. J Cardiopulm Rehabil Prev. 2020;40:302–
309. doi: 10.1097/HCR.0000000000000525
22. Kitzman DW, Haykowsky MR, Tomczak CJ. Making the case for skeletal
muscle myopathy and its contribution to exercise intolerance in heart fail-
ure with preserved ejection fraction. Circ Heart Fail. 2017;10:e004281. doi:
10.1161/CIRCHEARTFAILURE.117.004281
23. Carbone S, Billingsley HE, Rodriguez-Miguelez P, Kirkman DL, Garten R,
Franco RL, Lee D-C, Lavie CJ. Lean mass abnormalities in heart failure:
the role of sarcopenia, sarcopenic obesity, and cachexia. Curr Probl Cardiol.
2020;45:100417. doi: 10.1016/j.cpcardiol.2019.03.006
24. Selvaraj S, Kim J, Ansari BA, Zhao L, Cvijic ME, Fronheiser M, Mohan-
Rao Vanjarapu J, Kumar AA, Suri A, Yenigalla S, et al. Body composition,
natriuretic peptides, and adverse outcomes in heart failure with preserved
and reduced ejection fraction. JACC Cardiovasc Imaging. 2021;14:203–
215. doi: 10.1016/j.jcmg.2020.07.022
25. Billingsley HE, Hummel SL, Carbone S. The role of diet and nutrition in
heart failure: a state-of-the-art narrative review. Prog Cardiovasc Dis.
2020;63:538–551. doi: 10.1016/j.pcad.2020.08.004
26. Metter EJ, Talbot LA, Schrager M, Conwit R. Skeletal muscle strength as
a predictor of all-cause mortality in healthy men. J Gerontol Biol Sci. 2002;
57A:B359–B365. doi: 10.1093/gerona/57.10.b359
27. Pu C, Johnson M, Forman D, Hausdorff JM, Roubenoff R, Foldvari M,
Fielding RA, Singh MA. Randomized trial of progressive resistance train-
ing to counteract the myopathy of chronic heart failure. J Appl Physiol.
2001;90:2341–2350. doi: 10.1152/jappl.2001.90.6.2341
28. Mandic S, Tymchak W, Kim D, Daub B, Quinney HA, Taylor D,
Al-Kurtass S, Haykowsky MJ. Effects of aerobic or aerobic and resistance
training on cardiorespiratory and skeletal muscle function in heart failure:
a randomized controlled pilot trial. Clin Rehabil. 2009;23:207–216. doi:
10.1177/0269215508095362
29. Jewiss D, Ostman C, Smart NA. The effect of resistance training on clini-
cal outcomes in heart failure: a systematic review and meta-analysis. Int J
Cardiol. 2016;221:674–681. doi: 10.1016/j.ijcard.2016.07.046
30. Tucker WJ, Beaudry RI, Liang Y, Clark AM, Tomczak CR, Nelson MD,
Ellingsen O, Haykowsky MJ. Meta-analysis of exercise training on left
ventricular ejection fraction in heart failure with reduced ejection frac-
tion: a 10-year update. Prog Cardiovasc Dis. 2019;62:163–171. doi:
10.1016/j.pcad.2018.08.006
31. Schocken D, Arrieta M, Leaverton P, Ross EA. Prevalence and mortal-
ity rate of congestive heart failure in the United States. J Am Coll Cardiol.
1992;20:301–306. doi: 10.1016/0735-1097(92)90094-4
32. Rich MW, Beckham V, Wittenberg C, Leven CL, Freedland KE, Carney R. A
multidisciplinary intervention to prevent the readmission of elderly patients
with congestive heart failure. N Engl J Med. 1995;333:1190–1195. doi:
10.1056/NEJM199511023331806
33. Schroeder ET, Wang Y, Castaneda-Sceppa C, Cloutier G, Vallejo AF,
Kawakubo M, Jensky NE, Coomber S, Azen SP, Sattler FR. Reliability of
maximal voluntary muscle strength and power testing in older men. J Geron-
tol A Biol Sci Medl Sc. 2007;62:543–549. doi: 10.1093/gerona/62.5.543
34. Fragala MS, Anne M Kenny AM, George A Kuchel GA. Muscle qual-
ity in aging: a multi-dimensional approach to muscle functioning
with applications for treatment. Sports Med. 2015;45:641–658. doi:
10.1007/s40279-015-0305-z
35. Pavasini R, Guralnik J, Brown JC, di Bari M, Cesari M, Landi F, Vaes B,
Legrand D, Verghese J, Wang C, et al. Short physical performance battery
and all-cause mortality: systematic review and meta-analysis. BMC Med.
2016;14:215–215. doi: 10.1186/s12916-016-0763-7
36. Spertus J, Peterson E, Conard MW, Heidenreich PA, Krumholz HM,
Jones P, McCullough PA, Pina I, Tooley J, Weintraub WS, et al; Cardiovascular
February 2023 126
 Brubaker et al
Outcomes Research Consortium. Monitoring clinical changes in patients
with heart failure: a comparison of methods. Am Heart J. 2005;150:707–
715. doi: 10.1016/j.ahj.2004.12.010
37. Institute of Medicine (2005) dietary reference intakes for energy, carbo-
hydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids (Mac-
ronutrients). Washington DC: The National Academies Press. ISBN:
978-0-309-08525-0
38. Bopp M, Houston D, Lenchik L, Easter L, Kritchevsky S, Nicklas B. Lean
mass loss is associated with low protein intake during dietary-induced
weight loss in postmenopausal women. J Am Diet Assoc. 2008;108:
1216–1220. doi: 10.1016/j.jada.2008.04.017
39. Williams MA, Haskell WL, Ades PA, Amsterdam EA, Bittner V, Franklin
BA, Gulanick M, Laing ST, Stewart KJ; American Heart Association Council
on Clinical Cardiology. Resistance exercise in individuals with and without
cardiovascular disease: 2007 update: a scientific statement from the Ameri-
can Heart Association Council on Clinical Cardiology and Council on Nutri-
tion, Physical Activity, and Metabolism. Circulation. 2007;116:572–584. doi:
10.1161/CIRCULATIONAHA.107.185214
40. ACSM’s Guidelines for exercise testing and prescription. Philadelphia: Lippincott
Williams & Wilkins, 2021;11th edition. ISBN: 9781975150181, 197515018X
41. Fukuta H, Goto T, Wakami K, Ohte N. Effects of drug and exercise interven-
tion on functional capacity and quality of life in heart failure with preserved
ejection fraction: a meta-analysis of randomized controlled trials. Eur J Prev
Cardiol. 2016;23:78–85. doi: 10.1177/2047487314564729
42. Butler J, Khan MS, Mori C, Filippatos GS, Ponikowski P, Comin-Colet J,
Roubert B, Spertus JA, Anker SD. Minimal clinically important difference in
quality of life scores for patients with heart failure and reduced ejection frac-
tion. Eur J Heart Fail. 2020;22:999–1005. doi: 10.1002/ejhf.1810
43. Villareal DT, Aguirre L, Gurney AB, Waters DL, Sinacore DR, Colombo E,
Armamento-Villareal R, Qualls C. Aerobic or resistance exercise, or both,
in dieting obese older adults. N Engl J Med. 2017;376:1943–1955. doi:
10.1056/NEJMoa1616338
Downloaded from http://ahajournals.org by on June 7, 2024
Circ Heart Fail. 2023;16:e010161. DOI: 10.1161/CIRCHEARTFAILURE.122.010161
Resistance Training During CR+AT in HFpEF
44. Pandey A, Kitzman DW. Searching for the optimal exercise training regimen
in heart failure with preserved ejection fraction. JAMA. 2021;325:537–539.
doi: 10.1001/jama.2020.26347
45. Obokata M, Reddy Y, Pislaru SV, Melenovsky V, Borlaug BA. Evidence
supporting the existence of distinct obese phenotype of heart failure with
preserved ejection fraction. Circulation. 2017;136:6–19. doi: 10.1161/
CIRCULATIONAHA.116.026807
46. Nicklas BJ, Brinkley TE, Houston DK, Lyles MF, Hugenschmidt CE,
Beavers KM, Leng X. Effects of caloric restriction on cardiorespiratory fit-
ness, fatigue, and disability responses to aerobic exercise in older adults
with obesity: a randomized controlled trial. J Gerontol A Biol Sci Med Sci.
2019;74:1084–1090. doi: 10.1093/gerona/gly159
47. Shea MK, Nicklas BJ, Marsh AP, Houston DK, Miller GD, Isom S, Miller
ME, Carr JJ, Lyles MF, Harris TB, et al. The effect of pioglitazone and
resistance training on body composition in older men and women
undergoing hypocaloric weight loss. Obesity (Silver Spring). 2011;19:
1636–1646. doi: 10.1038/oby.2010.327
48. Goodpaster BH, Park SW, Harris TB, Kritchevsky SB, Nevitt M, Schwartz
AV, Simonsick EM, Tylavsky FA, Visser M, Newman AB. The loss of skeletal
muscle strength, mass, and quality in older adults: the health, aging and
body composition study. J Gerontol A Biol Sci Med Sci. 2006;61:1059–
1064. doi: 10.1093/gerona/61.10.1059
49. Newman A, Kupelian V, Visser M, Simonsick EM, Goodpaster BH,
Kritchevsky SB, Tylavsky FA, Rubin SM, Harris TB. Strength, but not mus-
cle mass, is associated with mortality in the health, aging and body com-
position study cohort. J Gerontol Biol Sci Med Sci. 2006;61A:72–77. doi:
10.1093/gerona/61.1.72
50. Mentz R, Whellan D, Reeves G, Pastva AM, Duncan P, Upadhya B, Nelson MB,
Chen H, Reed SD, Rosenberg PB, et al. Rehabilitation intervention in older
patients with acute heart failure with preserved versus reduced ejection
fraction. JACC Heart Fail. 2021;9(10):747–757. doi: 10.1016/j.jchf.2021.
05.007
February 2023 127