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. Author manuscript; available in PMC: 2014 May 1.
Published in final edited form as: Heart Lung Circ. 2013 Jan 20;22(5):328–340. doi: 10.1016/j.hlc.2012.12.006

Effects of Exercise Interventions on Peripheral Vascular Endothelial Vasoreactivity in Patients with Heart Failure with Reduced Ejection Fraction

Karen M Vuckovic a,*, Mariann R Piano a, Shane A Phillips b,c
PMCID: PMC3679497  NIHMSID: NIHMS437809  PMID: 23340198

Abstract

Changes in vascular function, such as endothelial dysfunction are linked to the progression of heart failure (HF) and poorer outcomes, such as increased hospitalisations. Exercise training may positively influence endothelial function in HF patients with reduced ejection fraction. The aim of this manuscript is to summarise HF studies evaluating the influence of exercise training on endothelial function as measured by flow mediated vasodilation as a primary outcome and to provide recommendations for future research studies designed to improve peripheral vascular function in HF. Databases were searched for studies published between 1995 and December 2011. Two reviewers determined eligibility and extracted information on study characteristics and quality, exercise interventions, and endothelial function. Eleven articles (N = 318 HF participants with an ejection fraction <40%) were eligible for full review. Aerobic, resistance, or combined exercise training improved endothelium-dependent vasodilation as measured by ultrasound or plethysmography. There is less evidence supporting improvement in endothelium-independent function with exercise training. Sample sizes were small and predominantly male. Future research is needed to address the best mode and optimal dose of exercise for all patients with HF including women and subgroups with specific co-morbidities.

Keywords: Heart failure, Exercise, Endothelium, Flow-mediated dilation

Introduction

Abnormalities in peripheral vasodilation, in particular endothelial dysfunction, contribute to the development and progression of heart failure (HF). Endothelial dysfunction may also be one of the mechanisms underlying exercise intolerance in HF. Endothelial dysfunction may result in impaired afterload reduction, alterations in vascular tone and abnormal responses to circulating stimuli, all of which can impact exercise capacity and tolerance. In addition, endothelial dysfunction is also associated with an increased risk for mortality in HF patients with reduced ejection fraction (HRrEF) <40% [13]. A growing body of evidence suggests exercise training improves exercise intolerance and endothelial dysfunction for patients with HFrEF [410]. Flow-mediated dilation (FMD) is a well-established measure of assessing endothelial function [11,12]. High-resolution ultrasound and plethysmography are commonly used to measure FMD in peripheral blood vessels (e.g., brachial artery) in response to exercise training. The aim of this manuscript is to summarise the prospective human HF studies evaluating the influence of exercise training on endothelial function as measured by FMD as a primary outcome and to provide recommendations for future research studies designed to improve peripheral vascular function in HF.

Methods

Search Strategy

We searched PubMed, CINAHL, and Cochrane databases (1995–December 2011) using a combination of the search terms “heart failure, congestive heart failure, exercise training, exercise, physical training, endothelium, and endothelial function.” Search criteria were set to include only human studies. The search yielded 64 citations. We excluded non-English articles and reviews. Forty-two articles were selected as potentially relevant and independently reviewed by two authors (K.V. and S.P.). Five articles were added after handsearching reference lists. Of these, 11 were met the following inclusion criteria: (1) sample population was patients with chronic HFrEF with ejection fraction (EF) <40%; (2) high-resolution ultrasound or plethysmography was used to assess peripheral vasoreactivity as a primary outcome following a period of weekly exercise and; (3) use of a prospective single-group experimental design, nonrandomised or randomised study design. Eligible studies used a weekly exercise intervention incorporating aerobic (endurance) and/or resistance (strength) training. The exercise training could be supervised or unsupervised and performed in an inpatient, outpatient, home-based, or combined setting. The study searching and selection process is summarised in Fig. 1.

Figure 1.

Figure 1

The summary of the literature search and selection process.

Data Extraction and Assessment of Methodological Quality

Data extraction was conducted independently by one reviewer (KV) and checked by a second author (SP). Any disagreements were settled by discussion or third author (MP). Relevant data related to the inclusion criteria (study design, sample characteristics, the frequency, duration, intensity and modality of exercise, outcomes), risk of bias (randomisation, blinding, selective outcome reporting) and results were extracted.

We did not rate the studies using a numerical quality score. Rather, we used a component approach and assessed key dimensions for each study. The quality of the studies were reviewed for clear definition of control and HF sample, baseline comparisons for parallel groups, risk of bias (e.g., group assignment, blinding of outcome assessment), control of confounding factors and statistical reporting. Given the nature of the studies, we did not expect subjects or study personnel who supervised the exercise sessions to be blinded to group assignment.

Results

Cohort Characteristics

Details of the 11 selected studies (N = 318 total HF subjects) are summarised in Table 1. Most studies recruited convenience samples. Sixty-seven percent (n = 7) exclusively enrolled men, while no study indicated race and ethnicity. The sample size across studies varied from 7 to 59 [13,17]. The majority of patients were New York Heart Association (NYHA) classes II–III patients with ischaemic heart disease; however, Miche et al. [20] recruited patients with NYHA class I–III HF, and Erbs et al. [22] specifically recruited subjects with ischaemic heart disease and advanced chronic HF (NYHA IIIb; n = 37). Most investigators required subjects to be “clinically stable,” i.e., no hospitalisations and optimised on medications for two [19,22] or three months [1517,21,23] prior to enrollment. Among studies, the range of the mean age was 44–75 years. One study [21] included patients with a mean age of 70 years and recruited patients >80 years of age (n = 12).

Table 1.

Summary of Study Characteristics.

Study Study Design and Participants HF Aetiology Outcomes, Limitations Confounders FMD Method Main Findings
Bank et al. [13]
  • 2-Group experimental design; both groups exercised

  • Mean EF 22.5 ± 3%; NYHA II/III

  • All male subjects (n = 7)

  • Mean age of healthy control group 40 ± 4 y (n = 11); exercise HF group 57 ± 5 y (n = 7)

  • Subjects were receiving diuretics, ACE/ARB, digoxin, nitrates, hydralazine, amiodarone, ASA

  • Medications stopped 24–48 h before study

  • All non-smokers

Idiopathic and
ischaemic CM
MAP, HR, forearm volume,
forearm blood flow measured
at baseline and post-exercise
in response to 5 min of
ischaemia, ACH and SNP in
trained and untrained arm
Limitation: significant
differences between
intervention group (older, all
male) and control group
(younger, male and female);
small sample size
Plethysmography:
Forearm
MAP, HR or forearm blood
volume did not significantly
change after handgrip exercises
for either group
In the healthy control group,
endothelium-dependent
vasodilation in response to ACH
increased following exercise
Flow-mediated dilation
increased only during peak
blood flow post-exercise in the
healthy control group
Endothelium-dependent and
flow-mediated vasodilation did
not significantly change
post-exercise compared with
baseline in the HF group
Endothelium-independent
vasodilation diameters did not
change post-exercise from
baseline in either group
Maiorana et al. [14]
  • Cross-over experimental design

  • Mean EF 26±3; NYHA I-III

  • All male subjects (n = 12)

  • Mean age of HF subjects 60±2 y (n = 12)

  • Subjects were receiving diuretics, ACE/ARB, digoxin, nitrates, hydralazine, anti-arrhythmics, ASA, warfarin, carvedilol

  • Medications not changed during study

  • All non-smokers

  • Data analysed by investigator blinded to subjects identity

Coronary heart
disease; idiopathic
CM
MAP, HR, HDL, LDL
Forearm blood flow response
at baseline and post-exercise
in response to 10 min of
ischaemia, ACH and SNP
Limitations: all male, small
sample size; data analysed by
change ratio; longer period
ischaemia
Plethysmography:
Radial artery
MAP, resting HR, HDL, and LDL
were not significantly different
between the trained (cycling and
resistance) and untrained
periods
Endothelium-dependent
vasodilation in response to ACH
showed a significant increase
post exercise training (p < 0.05,
2-way ANOVA)
Endothelium-independent
vasodilation assessed by forearm
blood flow increased
post-exercise training but did
not reach significance (p = 0.06)
Within-group comparisons for
endothelium-dependent
vasodilation and
endothelium-independent
vasodilation reached significance
when analysed by ratio (percent
change from preceding baseline
values) between the trained and
untrained periods (p < 0.05,
ANOVA)
Linke et al. [15]
  • Randomised clinical trial

  • Mean EF HF control group: 24±2%; HF exercise group: 26±3%; NYHA II/III

  • All male subjects (n = 22)

  • Mean age of control group 59±3 y (n = 11); exercise group 58 ± 2 y (n = 11)

  • Subjects were receiving diuretics, ACE/ARB, beta blockers, digoxin

  • Medications held >24 h

  • No medications changes 4 weeks prior to enrolment and throughout study

  • Currently not smoking

Ischaemic heart
disease; dilated CM
Vessel diameter at baseline
and post exercise in response
to 5 min of ischaemia, ACH
and NTG
Limitations: baseline vessel
diameter (3.42±0.12 mm) in
the intervention group was
significantly larger (p < 0.05)
compared with control group
(2.99 ± 0.13 mm); unclear if
investigators were blinded
Ultrasound:
Radial artery
Endothelium-dependent
vasodilation in response to ACH
significantly increased after 4
weeks of cycling (p < 0.001)
compared with baseline in the
exercise group; response to ACH
was unchanged in control group
Endothelium-independent
vasodilation was unchanged
from baseline in either group
Flow-mediated dilation diameter
significantly increased from
baseline in the treatment group
(374±57 μm to 570±76 μm;
p < 0.01); vessel diameter did not
change from baseline in the
control group
Kobayashi et al. [16]
  • Randomised clinical trial

  • Mean EF HF control group: 33±2%; HF exercise group: 29±2%; NYHA II/III

  • Male (n = 20); female (n = 8)

  • Mean age of HF control group 62±2 y (n = 14); HF exercise group 55±2 y (n = 14)

  • Subjects were receiving ACE/ARB, beta blockers, statins

  • Allowed changes in medications

  • Not currently smoking

  • Investigators analyzing data were blinded to treatment allocation

Ischaemic heart
disease; dilated CM
NE, ET-1, IL-6, BNP, baseline
diameter and blood flow in
brachial and tibial artery post
exercise in response to 5 min
of ischaemia in trained and
untrained limbs
Limitations: mean age and
peak VO2 differed between
control and exercise groups
(p < 0.05); smoking status of
subjects unclear; medications
changed during protocol;
vessel diameter
measurement inconsistent
Ultrasound:
Brachial artery
(non-exercised)
tibial artery
(exercised)
NE, ET-1, IL-6, and BNP levels
did not significantly change from
baseline parameters in either
group
Flow-mediated vasodilation did
not change from baseline in the
brachial or tibial artery of the
control group
Flow-mediated vasodilation in
the brachial artery did not
change from baseline in the HF
exercise group (4.34±0.45% vs.
4.34±0.43%)
Flow-mediated vasodilation in
the tibial artery significantly
increased from baseline in the
HF exercise group (3.64 ± 0.26%
vs. 6.44 ± 0.56%; p < 0.01)
Reactive hyperaemia (percent
increase in mean blood flow
after cuff deflation) did not
significantly change from
baseline in either group for the
upper or lower limb
Belardinelli et al. [17]
  • Randomised clinical trial

  • Mean EF HF control group: 28.1±5%; HF exercise group: 29.3±6%; NYHA II/III

  • All male subjects without prostatic disease (n = 59)

  • Mean age of HF control group 58±12 y (n = 29); HF exercise group 55±15 y (n = 30)

  • Subjects were receiving diuretics, ACE/ARB, beta blockers, digoxin, nitrates

  • Medications not changed

  • Smokers in treatment (n = 10) and control groups (n = 9)

  • Images were analysed independently by 2 researchers blinded to clinical status and each other’s interpretation (percent agreement 1.2±0.8% and 1.9±0.9%, respectively)

Ischaemic heart
disease; idiopathic
CM
CPET, QoL scores, sexual
activity profile, coronary risk
factors, vessel diameter in
response to 4.5 min of
ischaemia, ACH, and NTG
Limitations: all male; cardiac
risk factors not measured;
smokers and non-smokers
included
Ultrasound:
Brachial artery
CPET parameters, QoL and
sexual activity prolife scores
significantly improved in the
exercise group; no changes in
control group
Coronary risk factors improved
in the exercise group compared
with the control group after
training
Flow-mediated dilation diameter
improved only in the exercise
group (2.29±1.13% to
5.04±1.7%; p = 0.0001)
Endothelium-independent
vasodilation vessel diameter was
unchanged in either group
Parnell et al. [18]
  • Randomised clinical trial

  • Mean EF HF control group: 20.8±2.4%; HF exercise group: 21.1±2.5%; NYHA II/III

  • All male (n = 21)

  • Mean age of HF control group 54±3 y (n = 10); HF exercise group 55±3 y (n = 11)

  • Subjects were receiving diuretics, ACE/ARB, beta blockers, digoxin, ASA, warfarin

  • No medication changes 2 weeks prior to enrolment and throughout study

Ischaemic heart
disease; other
6 MW distance, forearm
blood flow in response to
ACH, SNP, L-arginine
transport (based on plasma
levels)
Limitations: all male;
differences at baseline in
triacylglycerol levels between
groups; smoking status of
subjects unknown; unclear if
different aspects of data
analysis were blinded
Plethysmography:
Forearm
6 MW distance increased from
baseline (496±21 m to
561±17 m; p = 0.005) in the
exercise group post aerobic and
light resistance training
Forearm blood flow response to
ACH and SNP significantly
increased from baseline (p = 0.01
and p = 0.006, respectively) in the
exercise group post exercise
L-Arginine transport increased
significantly in the exercise
group (p = 0.04) and positively
correlated with exercise training
(n = 10; r = 0.69, p = 0.02)
No significant differences were
found for 6 MW distance,
forearm blood flow, and
L-arginine transport from
baseline in the control group
Belardinelli et al. [19]
  • Randomised clinical trial

  • Mean EF HF control group: 33.6 ± 8%; HF exercise group 30.2±7%; NYHA II/III; all subjects had a device implantation within 3 months

  • All male (n = 52)

  • Control groups: ICD (n = 15), ICD/CRT (n = 15); exercise groups: ICD (n = 15), ICD/CRT (n = 10)

  • Mean age of control group 53±15 y (n = 30); exercise group 55±14 y (n = 22)

  • Subjects were receiving ACE/ARB, beta blockers

  • Medication was not changed during the study

  • Echocardiographic studies were read twice and values averaged

  • Analysis of FMD images as described in 2005 study by same author

All ischaemic heart
disease
CPET and echocardiographic
parameters, QoL scores,
vessel diameter in response
to 4.5 min of ischaemia, NTG
Limitations: all male sample;
smoking status unclear
Ultrasound:
Brachial artery
CPET parameters significantly
improved in the exercise group
post exercise; no significant
changes in the control groups
QoL scores significantly
improved in the ICD/CRT
exercise group (p < 0.001)
Echocardiographic parameters
showed the greatest
improvement in the ICD/CRT
exercise group compared with
CRT device group or both
control groups
No significant differences in the
endothelium-independent
vasodilation vessel diameter
from baseline in any group
Flow-mediated dilation vessel
diameter significantly improved
in the exercise group regardless
of the type of device therapy
Miche et al. [20]
  • 2-Group experimental design

  • Mean EF diabetic group: 24.2 ± 3.4; non-diabetic group: 22.9±3.8%; NYHA I-III

  • Male (n = 36) female (n = 8)

  • HF patients with insulin-treated type 2 diabetes (n = 20); and HF patients without diabetes (n = 22)

  • Mean age of diabetic group 67±6 y (n = 20); non-diabetic group 68±10 y (n = 22)

  • Subjects were receiving diuretics, ACE/ARB, beta blockers, digoxin, anti-coagulants, statins

  • Medications were held 24 h prior to ultrasound

Ischaemic heart
disease; other
CPET and echocardiographic
parameters, QoL scores,
vessel diameter in response
to 4.5 min of ischaemia, NTG
Limitations: smoking status
unknown; unclear if different
aspects of data analysis were
blinded; medications were
changed during the study
Ultrasound:
Brachial artery
LVEF and VO2 max significantly
increased post exercise for both
groups (df 1, F = 0.001; p ≤ 0.05)
Endothelium-independent
vasodilation did not significantly
improve post exercise in the
diabetic (10.5 ± 5.6.6% vs.
8.7 ± 4.1%) or non-diabetic
(13.2 ± 5.8% vs. 12.3 ± 6.3%)
group
Flow-mediated dilation vessel
diameter did not significantly
change from baseline post
exercise in the diabetic
(5.1±3.6% vs. 4.9±2.5%) or
non-diabetic (6.8±4.5% vs.
7.6±4.0%) group
No significant correlation
between the change in
flow-mediated dilation and VO2
max
Wisløff et al. [21]
  • Randomised control trial; stratified by gender and age into 3 groups (AIT n = 9, MCT n = 9, control n = 9)

  • Mean EF HF control: 26.2±8.0%; HF MCT group: 32.8±4.8%; HF AIT group: 28.0±7.3%; all with post infarct HF; NYHA not reported

  • Male (n = 20) female (n = 7)

  • Mean age 75.5±11 y (n = 27)

  • Subjects were receiving diuretics, ACE/ARB, beta blockers, digoxin, long-acting nitrates, ASA, warfarin, statins

  • Medication not changed

  • Echocardiography was performed by 2 cardiologists blinded to group assignment

Ischaemic aetiology post infarct on beta blockers CPET and echocardiographic
parameters, QoL scores,
skeletal muscle metabolism,
Ca++ reuptake assay, vessel
diameter in response to 5 min
of ischaemia, NTG
Limitation: small
predominantly male sample;
control group received more
than usual care-met every 3
weeks for 47 min of exercise;
smoking status unknown;
generalisability limited
Ultrasound:
Brachial artery
Peak VO2 increased post exercise
in the AIT and MCT group (46%
and 14%, respectively; p = 0.21)
QoL scores improved post
exercise in the AIT (p < 0.001)
and MCT (p < 0.01) groups; no
change in the control group
Echocardiographic parameters
improved and skeletal muscle
Ca++ reuptake increased post
exercise in the AIT group
Flow-mediated dilation
improved after training for the
intervention groups but was
greater for AIT group than MCT
group (p < 0.05)
Endothelium-independent
vasodilation diameter did not
change for any group
Erbs et al. [22]
  • Randomised control trial

  • EF < 30%; LV end-diastolic diameter ≥60 mm; NYHA IIIba; peak O2 uptake ≤20 mL/min/kg

  • All males ≤70 y (n = 37)

  • Mean age of HF control group 62±10 y (n = 19); mean age HF exercise group 60±11 y (n = 18)

  • Subjects were receiving diuretics, ACE/ARB, beta blockers, digoxin, anti-coagulation, statins, aldosterone antagonist, allopurinol

  • Medications continued but discontinued 24 h prior to ultrasound

  • Non-smokers

  • One investigator blinded to patient identity, group assignment and intervention status analysed FMD data

Ischaemic heart
disease
CPET and echocardiographic
parameters, measures of
oxidative stress and
neorevascularisation of
skeletal muscle, vessel
diameter in response to 5 min
of ischaemia
Limitations: HF exercise
group had a higher incidence
of atrial fibrillation; 5 subjects
had cardiac cachexia; unclear
if medications changed;
radial artery diameter was
blunted at baseline; flow
velocity was at rest and at
peak hyperaemia were not
determined;
endothelium-independent
vasodilation not studied
Ultrasound:
Radial artery
VO2 max, ventilatory threshold,
LV performance measures
improved from baseline in the
exercise group; no significant
changes in the CPET of
echocardiographic parameters
for the control group
Flow-mediated dilation
significantly improved from
baseline in the exercise group
(absolute change in vessel
diameter: 415±86 μm; percent
change 6.1±2.5% to 13.6±2.2%;
p < 0.01)
Increased number of progenitor
cells, capillary density, and
neorevascularisation growth
factors with a reduction in
markers of oxidative stress
within the treatment group; no
changes for these factors in the
control group
Dean et al., 2011 [23]
  • Single group experimental design

  • Mean EF 10.9 ± 1.8%b

  • Males (n = 7) and females (n = 2) with advanced HF on continuous inotropic support for end-stage HF (n = 9)

  • Mean age 44.11 ± 4.79 yb range 24–58 y

  • Subjects were receiving diuretics, ACE/ARB, beta blockers, digoxin, nitrates, statins, anti-coagulation

  • Medications continued

Idiopathic,
ischaemic,
congenital,
valvular, primary
pulmonary HTN,
postpartum CM
Forearm maximal voluntary
contraction, vessel diameter,
blood flow measured at
baseline and post-exercise in
response to 2 min of
ischaemia
Limitations: all male, no
control group, subjects had
advanced HF of various
aetiologies; shorter occlusion
time to induce ischaemia;
smoking status unknown;
unclear if different aspects of
data analysis were blinded
Ultrasound:
Brachial artery
Muscle strength and
endothelium-dependent
vasodilation at baseline did not
significantly change post
exercise
Pre exercise baseline hyperaemic
responses increased at 10 s and
then decreased; overall decrease
in diameter of 0.13 ± 0.04 mm at
1 min after cuff release.
Post-exercise flow-mediated
vasodilation diameter increased
(1.01% ± 0.99%) at 1 min after
cuff release

ACEI, angiotensin-converting enzyme inhibitor; AIT, aerobic interval training; ARB, angiotensin receptor blocker; ASA, aspirin; CRT, cardiac resynchronisation therapy; ICD, internal cardiodefibrillator; CM, cardiomyopathy; IHD, ischaemic heart diseases; EF, ejection fraction; ET-1, endothelin-1; NS, non-significant; NO, nitric oxide; ACH, acetylcholine; NTG, nitroglycerine; HF, heart failure; HR, heart rate; HTN, hypertension; IL-6, interleukin-6; CAD, coronary artery disease; MAP, mean arterial pressure; MCT, moderate continuous training; NE, norepinephrine; SNP, sodium nitroprusside; y, year.

a

NYHA IIIb recent history of dyspnoea.

b

Reported as SEM.

Types of Study Design

Among the selected studies, there were seven randomised control trials, 2- two-group experimental studies, one single-group experimental study, and one crossover study. In addition to FMD, the majority of investigators (n = 8) also examined multiple outcomes (e.g., quality of life, maximal oxygen consumption), however only findings related to the effects of exercise on FMD are reported herein.

Quality of Studies

The assessment of the methodological quality of the study is dependent upon the extent that the authors provide information about the design and analysis of the study. None of the randomised studies reported using intention to treat analysis; often missing data and attrition were not addressed. All investigators reported the standard deviation or standard error of the point estimates for various outcome variables related to vasoreactivity but statistical values (e.g., F score) and confidence intervals were not always included. Therefore considering the heterogeneity of the data, we did not perform a meta-analysis. The assessment of study quality is summarised in Table 2.

Table 2.

Summary of Individual Components Related to the Quality of the Studies.

Study Eligibility Criteria
Specified
Random Allocation Concealed
Allocation
Baseline
Comparability
Blinded
Assessors
Missing Data Between-Group
Comparisons
Point Estimates and
Variability
Randomised controlled trials
Maiorana et al. [14] + + +SE
Linke et al. [15] + + + +SEM
Kobayashiet al. [16] + + + + +SE
Belardinelli et al. [17] + + + +SD
Parnell et al. [18] + + + + +SEM
Belardinelli et al. [19] + + + + +SD
Wisløff et al. [21] + + + + +SD
Erbs et al. [22] + + + + +SD
One and two group experimental design
Bank et al. [13] N/A N/A + + + +SE
Miche et al. [20] N/A N/A + + +SD
Dean et al. [23] a N/A N/A N/A N/A +SEM

SD, standard deviation; SE, standard error; SEM, standard error of mean.

a

One group experimental design.

Controlling Confounding Variables

There are several confounding variables, such as medication and smoking, as well as co-morbid conditions that may influence vasoreactivity. Study protocols differed with respect to administering/withholding medications and including/excluding active smokers. Medications were continued but withheld for 24 h prior to the vascular measures [13,15,22]; continued at the same dose throughout the duration of the study (not withheld) [14,1719,21,23]; or allowed to change as needed during the study period [16,20]. The majority of studies excluded active smokers [1316,22], whereas other studies did not address smoking status [1821,23]. Belardinelli [17] enrolled smokers in both the control (n = 9) and the exercise (n = 10) groups. In addition, most of the investigators included subjects with co-morbidities; however investigators controlled for confounding co-morbidities in a number of ways. Some investigators excluded potential subjects with hypertension [17,18,22], valvular disease [17,22] or unstable angina [17,21,22]. Others [14,15] set specific parameters such as blood pressure readings >160/90 mmHg or total cholesterol level >6 mmol L as exclusion criteria. Belardinelli [17] compared the incidence of several co-morbidities between the exercise and control groups at baseline while Kobayashi [16] only reported the between group incidence of atrial fibrillation. Two studies did not address co-morbidities [19,23]. It should be noted that changes in endothelial function were found in these studies in spite of any possible effects of exercise on any individual comorbidities associated with HF.

Exercise Training Protocols

Exercise protocols varied across the studies, with cycle ergometry as the most common form of aerobic exercise (Table 3). Exercise intensity (determined by baseline stress testing) ranged from 50% to 95% of peak heart rate [18,21]. Two studies used a four-week handgrip resistance training program at varying intensities [13,23]. Others used combined training modes, such as Maiorana et al., who used resistance training (circuit) with aerobic training (cycling and treadmill walking) for eight weeks at an intensity of 70–85% of peak HR [14]. Dean et al. combined free-weights with handgrip training [23]. The frequency of exercise training varied from short intervals such as cycling for 10 min six times per day [15] to hour long sessions five to seven times/week [18]. The most common frequency of exercise was three times/week. Duration of training ranged from four weeks [13,15,20,23] to 12 weeks [16,21,22]. Across all studies, the initial exercise sessions were supervised.

Table 3.

Summary of Exercise Protocols.

Study Type of Exercise Duration of
Training
Intensity
Bank et al. [13] Resistance (handgrip)
Non-dominant forearm 4 times/wk
4 wks 30% of maximal hand grip strength at
30 grips per min
Maiorana et al. [14] Combination training (resistance
circuits, cycling)
7 resistance circuits (upper and lower
limbs) alternating with 8 aerobic
(cycling) stations each performed for
45 s, then 5 min of treadmill walking;
8 wks of three 1-h training sessions
8 wks Aerobic: 70–85% of peak HR;
resistance: maintained at 55–65% of
pre-training MVC
Linke et al. [15] Aerobic (cycling)
6 times per day for 10 min
4 wks 70% peak oxygen consumption at
ventilatory threshold
Kobayashi et al. [16] Aerobic (computerised cycling)
2–3 days/wk in two 15-min sessions per
day for 3 months
12 wks Maintain HR to the ventilatory
threshold for 15 min each session; if HR
irregular exercise speed at 13 on Borg
scale
Belardinelli et al. [17] Aerobic (cycling)
3 times/wk for 1 h (15 min stretching,
40 min of cycling)
8 wks 60% of peak VO2
Parnell et al. [18] Combination training (walking,
weights, cycling)
Walking, light hand weights, cycling 3
times/wk supplemented with
home-based exercises to increase
duration from three 30-min/wk to
60-min per day for 5–7 days/wk
8 wks 50–60% pre-determined maximal HR
Belardinelli et al. [19] Aerobic (cycling)
3 times/wk for 1 h (15 min stretching,
40 min of cycling)
8 wks 60% of peak VO2
Miche et al. [20] Combination (cycling and weights)
Aerobic (cycling) 3 times/wk and
muscle strength training 2 times/wk
4 wks 60–80% peak VO2
Wisløff et al. [21] Aerobic (uphill walking) 2 times a week
and 1 weekly session at home
AIT: 10-min warm-up at 50–60% peak
HR; walked at 4 min intervals at 90–95%
of peak HR; each interval separated by
3 min of walking at 50–70% of peak HR
MCT: walked continuously at 70–75%
of peak HR for 47 min; incline adjusted
to maintain target HR
12 wks Aerobic interval: 90–95% of peak HR
Moderate continuous: 70–75% of peak
HR
Serum lactate levels ensured different
intensities of exercise were achieved
Erbs et al. [22] Aerobic (cycling)
3 wks: 3–6 times per day for 5–20 min
12 wks: 20–30 min per day
12 wks HR reached at 50% of VO2 max for
3 wks
Then HR reached at 60% of VO2 max at
home
Dean et al. [23] Resistance (handgrip, free weights)
1 set of 6–10 repetitions at 60% for 2
days progressing to 6 sets of 6–10
repetitions at 70% to 80% of MVC
4 wks 60% of MVC set using hand grip
dynamometer
Weight determined by whatever the
patient could lift comfortably

wks, weeks; min, minute; h, hour; HR, heart rate; s, seconds; AIT, aerobic interval training; MCT, moderate continuous training; MVC, maximal voluntary contraction; VO2, peak oxygen consumption.

Notably, one randomised study was designed to determine if aerobic interval training was more effective than moderate continuous training to reverse peripheral vessel remodelling [21]. Wisløff et al. [21] randomised subjects with a reduced EF (<40%) who were prescribed beta blockers following a myocardial infarction into aerobic interval or moderate continuous training groups. Both groups showed improved FMD diameters; however, the improvement in the aerobic group was significantly greater (Table 1).

In addition to supervising subjects at the onset of training, several investigators monitored subject performance using self-report, serum lactate levels, or computers connected to the cycle ergometer to determine continued adherence to the exercise protocols. Investigators commonly reported that the exercise groups received education/instruction about exercise training, but the instructor (physical therapist, nurse, exercise physiologist), format and length of instruction, and delivery method (individual vs. group setting) pertaining to the education/instruction were not discussed. These are important factors that may potentially influence the subjects’ ability to follow and comprehend the protocol. In general, follow-up did not extend beyond completion of the exercise training period. An exception was the study by Belardinelli [19], in which follow-up continued after completion of exercise training for an additional 24 ± 6 months or until a cardiac event occurred.

Vasoreactivity Methods

Imaging with high-resolution ultrasound and plethysmography (Table 1) were used to directly assess vasoreactivity (i.e., endothelium-dependent and endothelium-independent vasodilation in the peripheral circulation). All studies measured vasoreactivity at two time points: baseline (pre-exercise) and upon completion of the training period (post-exercise). The most common method to measure vasoreactivity was ultrasound using the brachial or radial artery [1517,1923]. Three studies measured vasoreactivity using plethysmography in the forearm [13,18] or radial artery [14]. The exercise study protocols with regards to exercise frequency and type, duration, and intensity are summarised in Table 3.

Vascular Effects of Exercise Training

Collectively, results from the studies indicate significant improvement in endothelium-dependent vasodilation after aerobic, resistance, or combination exercise training [1419,2123], with the exception of two studies [13,20] (Table 1 and Fig. 2). Miche et al. [20] examined the effect of a four week combined exercise training program (i.e., ergometric strength and walking exercises) in HF subjects with and without type 2 diabetes mellitus (DM) and found no statistically significant training effect on endothelial function in either DM HFrEF group (Table 1). Likewise, Bank et al. [13] found non-significant improvement in endothelial function following four weeks of handgrip exercises in subjects with HF, although the healthy control subjects in this study showed significant improvement in endothelium-dependent function [13].

Figure 2.

Figure 2

Graphical plot of representation of Table 1 study data. Values (symbols) are percent change (pre-exercise values – post exercise values/baseline values) and were calculated using data values reported for each of the studies summarised in Table 1, with the exception of Belardinelli et al. [19], Wisløff et al. [21] and Dean et al. [23] studies. The results from the former studies were not included since data was reported in figures. Also the percent change value for the Kobayashi et al. study reflects those found using the tibial artery. Numbers in parentheses designate study reference number and *changes were significant.

Endothelium-independent vasodilation, as determined by the response of the vascular smooth muscle to a direct vasodilator stimulus (nitroglycerine or nitroprusside), was measured in nine of the studies (Table 1). Of these, the findings from seven studies did not show a significant change in endothelium-independent vasodilation. However, two studies [17,18] which used plethysmography to measure the response to nitroprusside (SNP) after eight weeks of training demonstrated improved endothelium-independent vasodilation after exercise. Maiorana et al. [14] showed statistically significant within-group differences analysing data using absolute blood flows and change ratio of blood flow (expressed as percent change in blood flow of the arm infused with medication compared with the control arm), while Parnell [18] reported a significant within-group difference in forearm blood flow with escalating doses of SNP (AUC, p = 0.006) following exercise training.

Discussion

Taken together, the findings of this review indicate that several types of exercise training (aerobic, resistance, and combined) of variable duration (4–16 weeks) improved endothelium-dependent vasodilation. Furthermore, this finding was not age-dependent, NYHA class or HF aetiology dependent (Table 1). Our findings are consistent with other studies and reviews, which reported that exercise training improved endothelium-dependent function in patients with HFrEF [59].

Most studies reported herein did not find exercise training effects on endothelium-independent vasodilation except for two reports that utilised combined aerobic with resistance training for eight weeks [14,18]. It is possible that the duration of training and combination of strength and aerobic exercise may have altered endothelium-independent vasodilation. For example, there were three other studies that employed 12 weeks of aerobic training with no changes in endothelium-independent dilation [15,21,22]. In another study that combined aerobic (cycling) and strength training for four weeks there was no change in endothelium-independent vasodilation. Therefore, the mechanisms of the effects of exercise training on endothelium-independent function will require further exploration. Studies designed to assess FMD on a weekly basis during the exercise training period or hourly following acute exercise may help to understand these mechanisms. Additional reasons for the lack of improvement in endothelium-independent vasodilation may be inadequate delivery of blood to exercising skeletal muscle and reduced muscle sensitivity to nitric oxide [26]. The first point has been widely addressed in the literature [4,25]. Regarding the latter, investigators have suggested that the response of vascular smooth muscle in individuals who regularly take nitrate-based medications may attenuate to NO-mediated and cyclic guanosine monophosphate (cGMP) stimuli [27]. Five of the studies reviewed included HF patients receiving nitrates [14,17,20,21,23]. And one of the latter studies as noted above found significant improvements in endothelium-independent vasodilation [14]. Based on the results from this review, it is not clear that the response of vascular smooth muscle is affected by nitrate medications or that exercise training can improve this response. Nitrate use may need to be a consideration when using endothelium-independent vasodilation as an outcome variable. Finally, it is thought that the loss of endothelium-dependent vasodilation occurs early in the development of cardiovascular disease, but it is not clear if and when endothelium-independent vasodilation is reduced [24,25].

Overall, the common limitations of the studies included in this review were small sample sizes that limit the ability to control for all the co-morbidities that might confound the results. Other limitations included: (1) a small number of women and lack of ethnic minorities in the population of study, (2) short duration of exercise programs, (3) inability to extrapolate supervised training at a rehabilitation facility to activity at home, (4) lack of a quantification of exercise intensity in the home-based interventions. However, given the complexity of exercise studies, longitudinal follow-up and patient population, HFrEF, it is not unexpected that sample sizes were small. In this review, most studies [16,17,19,22,23] were published after 2002 and utilised ultrasound imaging guidelines/techniques published by Corretti and colleagues [28]. Use of FMD measurement guidelines [28] reduces the likelihood of variability and inconsistencies in the technical aspects of FMD measurement. Corretti et al. [11,2830] recommend standardised schema for collecting and reporting FMD data, which allows for aggregating and comparing different published data, determining effect size and performing meta-analysis.

Although our review was focused on evaluating the influence of exercise on endothelial function, many of the studies reviewed herein also considered the effects of exercise training on patient safety, as well as potential issues related to exercise adherence. Ventricular arrhythmias, common in this patient population, were reported in one study [19], and the arrhythmias occurred only in the untrained control group (53%; n = 15) during the follow-up period. Among the studies, one death from cardiovascular causes occurred in a control group [22] and one in an exercise group [21]. These findings support those from HF-ACTION [31], which found that aerobic exercise was safe and improved exercise capacity even in patients with NYHA IV disease or following device implantation. However, findings from HF-ACTION also indicated that adherence to exercise over the three-year study period decreased over time. In this review, in studies that reported attrition, there were no differences in between control and exercise groups during the training period (4–12 weeks). Monitoring adherence to exercise programs/interventions is a critical aspect to both short- and long-term exercise studies, but clearly more challenging in long-term and unsupervised exercise trials. Future studies may need to test the added benefit of different types of motivational (group vs. individual exercise sessions) and lifestyle adherence strategies [3234].

As noted above, different types of exercise training (aerobic, resistance, and combined) had a positive effect on endothelial function. However, different types of exercise and protocols were used making it difficult to recommend the optimal exercise protocol for patients with HFrEF (NYHA I-III). Also, these results need to be interpreted in view of the limitations (small, predominantly male samples) and study characteristics (designed to examine special populations such as erectile dysfunction, advanced disease, and device therapy), which restrict generalisability. Therefore, it remains unclear as to which type of aerobic training (cycling vs. walking) is associated with the best effects on endothelial function. It is also remains unknown if combinations of programs involving walking or cycling plus resistance exercise are more effective than aerobic exercise alone on endothelial function because many of the studies included in this review did not compare exercise modes (Tables 1 and 3).

Recently, Anagnostakou et al. [35] examined the effects of combined interval and strength training (54 ± 10 years; n = 14) compared with interval training alone (52 ± 11 years; n = 14) on FMD in a predominantly male sample (82%; n = 23) with HF (EF < 45%) in a 12-week protocol. The investigators found significant increases in brachial artery diameter analysed as absolute change (difference in artery diameter before and after occlusion) and relative change (percentage of relative change in artery diameter before and after occlusion) between groups (p = 0.02; p = 0.03 respectively) and concluded that combined training had a greater effect on vasoreactivity than interval training alone. The authors acknowledge several limitations to the study, including that the EF was >50% in four subjects. Thus, this study did not meet the inclusion criteria for this review but is important because it compares the effectiveness of two types of exercise.

Conclusion

The findings of this review indicate that different types of exercise training (aerobic, resistance, and combined) of variable duration (4–16 weeks) in HFrEF improved endothelium-dependent vasodilation. However, few studies reported positive exercise effects on endothelium-independent vasodilation. The latter is difficult to explain. The optimal training intensity and duration, and the added value of resistance exercise along with aerobic training, remain to be determined in patients with HFrEF. Optimizing exercise training is a complex issue since HF is a heterogeneous syndrome. Patients often have co-morbidities which may affect the peripheral vasculature and in turn, exercise capacity. Also findings from studies with HFrEF patients cannot be extrapolated to all patients with HF such as those with preserved ejection fraction HF. The contribution of endothelial dysfunction to the abnormalities in the peripheral circulation of HF is well established. In this context, measurement of endothelial function remains important and should be used as an endpoint or variable in clinical trials and investigations.

Acknowledgements

We acknowledge the Midwest Roybal Center which is supported by a center grant from the National Institute on Aging/NIH (PI: Susan L. Hughes, DSW; Grant 5P30AG022849-07; UIC PAF # 2009-02182; Parent Protocol for the center grant – UIC Protocol #2009-0668). The authors thank Kevin Grandfield, Publication Manager for the UIC Department of Biobehavioral Health Science, for editing assistance.

Footnotes

Conflict of interest None.

Support: Dr. Phillips is supported by National Institutes of Health (Grant # HL85614).

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