Superior cardiovascular effect of aerobic interval training versus moderate continuous training in heart failure patients: a randomized study.

Abstract

Exercise training reduces the symptoms of chronic heart failure. Which exercise intensity yields maximal beneficial adaptations is controversial. Furthermore, the incidence of chronic heart failure increases with advanced age; it has been reported that 88% and 49% of patients with a first diagnosis of chronic heart failure are >65 and >80 years old, respectively. Despite this, most previous studies have excluded patients with an age >70 years. Our objective was to compare training programs with moderate versus high exercise intensity with regard to variables associated with cardiovascular function and prognosis in patients with postinfarction heart failure.
Twenty-seven patients with stable postinfarction heart failure who were undergoing optimal medical treatment, including beta-blockers and angiotensin-converting enzyme inhibitors (aged 75.5+/-11.1 years; left ventricular [LV] ejection fraction 29%; VO2peak 13 mL x kg(-1) x min(-1)) were randomized to either moderate continuous training (70% of highest measured heart rate, ie, peak heart rate) or aerobic interval training (95% of peak heart rate) 3 times per week for 12 weeks or to a control group that received standard advice regarding physical activity. VO2peak increased more with aerobic interval training than moderate continuous training (46% versus 14%, P<0.001) and was associated with reverse LV remodeling. LV end-diastolic and end-systolic volumes declined with aerobic interval training only, by 18% and 25%, respectively; LV ejection fraction increased 35%, and pro-brain natriuretic peptide decreased 40%. Improvement in brachial artery flow-mediated dilation (endothelial function) was greater with aerobic interval training, and mitochondrial function in lateral vastus muscle increased with aerobic interval training only. The MacNew global score for quality of life in cardiovascular disease increased in both exercise groups. No changes occurred in the control group.
Exercise intensity was an important factor for reversing LV remodeling and improving aerobic capacity, endothelial function, and quality of life in patients with postinfarction heart failure. These findings may have important implications for exercise training in rehabilitation programs and future studies.

Full text

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ISSN: 1524-4539
Copyright © 2007 American Heart Association. All rights reserved. Print ISSN: 0009-7322. Online
72514
Circulation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX
DOI: 10.1161/CIRCULATIONAHA.106.675041
2007;115;3086-3094; originally published online Jun 4, 2007;
Circulation
Terje Skjærpe
Vibeke Videm, Anja Bye, Godfrey L. Smith, Sonia M. Najjar, Øyvind Ellingsen and
Per Magnus Haram, Arnt Erik Tjønna, Jan Helgerud, Stig A. Slørdahl, Sang Jun Lee,
Ulrik Wisløff, Asbjørn Støylen, Jan P. Loennechen, Morten Bruvold, Øivind Rognmo,

Continuous Training in Heart Failure Patients: A Randomized Study
Superior Cardiovascular Effect of Aerobic Interval Training Versus Moderate
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Superior Cardiovascular Effect of Aerobic Interval
Training Versus Moderate Continuous Training in Heart
Failure Patients
A Randomized Study
Ulrik Wisløff, PhD; Asbjørn Støylen, MD, PhD; Jan P. Loennechen, MD, PhD; Morten Bruvold, MSc;
Øivind Rognmo, MSc; Per Magnus Haram, MD, PhD; Arnt Erik Tjønna, MSc; Jan Helgerud, PhD;
Stig A. Slørdahl, MD, PhD; Sang Jun Lee, PhD; Vibeke Videm, MD, PhD; Anja Bye, MSc;
Godfrey L. Smith, PhD; Sonia M. Najjar, PhD; Øyvind Ellingsen, MD, PhD; Terje Skjærpe, MD, PhD
Background—Exercise training reduces the symptoms of chronic heart failure. Which exercise intensity yields maximal
beneficial adaptations is controversial. Furthermore, the incidence of chronic heart failure increases with advanced age;
it has been reported that 88% and 49% of patients with a first diagnosis of chronic heart failure are ?65 and ?80 years
old, respectively. Despite this, most previous studies have excluded patients with an age ?70 years. Our objective was
to compare training programs with moderate versus high exercise intensity with regard to variables associated with
cardiovascular function and prognosis in patients with postinfarction heart failure.
Methods and Results—Twenty-seven patients with stable postinfarction heart failure who were undergoing optimal
medical treatment, including ?-blockers and angiotensin-converting enzyme inhibitors (aged 75.5?11.1 years; left
ventricular [LV] ejection fraction 29%; V˙O2peak13 mL · kg?1· min?1) were randomized to either moderate continuous
training (70% of highest measured heart rate, ie, peak heart rate) or aerobic interval training (95% of peak heart rate)
3 times per week for 12 weeks or to a control group that received standard advice regarding physical activity. V˙O2peak
increased more with aerobic interval training than moderate continuous training (46% versus 14%, P?0.001) and was
associated with reverse LV remodeling. LV end-diastolic and end-systolic volumes declined with aerobic interval
training only, by 18% and 25%, respectively; LV ejection fraction increased 35%, and pro-brain natriuretic peptide
decreased 40%. Improvement in brachial artery flow-mediated dilation (endothelial function) was greater with aerobic
interval training, and mitochondrial function in lateral vastus muscle increased with aerobic interval training only. The
MacNew global score for quality of life in cardiovascular disease increased in both exercise groups. No changes
occurred in the control group.
Conclusions—Exercise intensity was an important factor for reversing LV remodeling and improving aerobic capacity,
endothelial function, and quality of life in patients with postinfarction heart failure. These findings may have important
implications for exercise training in rehabilitation programs and future studies. (Circulation. 2007;115:3086-3094.)
Key Words: endothelium ? exercise ? remodeling ? heart failure
I
cular disease, even for those with severely impaired cardiac
function, and that physical inactivity accelerates the severity
of heart failure.1,2Peak aerobic exercise capacity directly
measured as peak oxygen uptake (V˙O2peak) was recently found
to be the single best predictor of both cardiac and all-cause
n recent years, there has been a growing consensus that
exercise has beneficial effects in patients with cardiovas-
Editorial p 3042
Clinical Perspective p 3094
deaths among patients with established cardiovascular dis-
ease1,2; however, there is still controversy regarding the level
and format of exercise that can yield optimal beneficial
effects.3Several lines of evidence suggest greater aerobic and
Received November 9, 2006; accepted March 30, 2007.
From the Department of Circulation and Medical Imaging (U.W., A.S., M.B., Ø.R., P.M.H., A.E.T., J.H., S.A.S., A.B., Ø.E.) and Department of
Laboratory Medicine (V.V.), Children’s and Women’s Health, Norwegian University of Science and Technology, Trondheim, Norway; Department of
Cardiology (U.W., A.S., J.P.L., Ø.E., T.S.) and Department of Immunology and Transfusion Medicine (V.V.), St. Olav’s Hospital, Trondheim, Norway;
Institute of Biomedical and Life Sciences (G.L.S.), University of Glasgow, United Kingdom; and Department of Physiology, Pharmacology, Metabolism
and Cardiovascular Sciences (S.J.L., S.M.N.), Medical University of Ohio, Toledo, Ohio.
Clinical trial registration information—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00218933.
Correspondence to Ulrik Wisløff, PhD, Department of Circulation and Medical Imaging, Norwegian University of Science and Technology, Olav
Kyrres gt. 9, 7489 Trondheim, Norway. E-mail ulrik.wisloff@ntnu.no
© 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.orgDOI: 10.1161/CIRCULATIONAHA.106.675041
3086
Exercise Physiology
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cardiovascular adaptations after high-intensity exercise than
with low and moderate levels in patients with coronary artery
disease,4chronic heart failure,5,6or left ventricular (LV)
dysfunction function7and in healthy subjects.8Exercise
training at an intensity of ?90% of V˙O2peakis in the upper
range of current guidelines for humans.3This level of aerobic
exercise can be achieved in an interval-training format in both
humans and animal models. The rationale for interval training
is that it allows for rest periods that make it possible for
patients with heart failure to complete short work periods at
a higher intensity (which challenges the heart’s pumping
ability) than would be possible during continuous exercise.
Aerobic interval training (AIT) involving periods at 90% of
V˙O2peakhas been shown to rescue impaired cardiomyocyte
contractility, attenuate myocardial hypertrophy, and reduce
myocardial expression of atrial natriuretic peptide in a rat
model of postinfarction heart failure.9The beneficial effects
on cardiac remodeling and myocyte function were similar to
those observed with the angiotensin II receptor blocker
losartan,10which indicates that AIT might be a potent
modifier of postinfarction heart failure. We therefore hypoth-
esized that AIT is more effective than moderate continuous
training (MCT) in enhancing cardiovascular fitness and
reversing myocardial remodeling in patients undergoing op-
timal treatment for stable heart failure after a myocardial
infarction.
Methods
Patients
We enrolled 27 consecutive patients (aged 75.5?11.1 years) with
postinfarction heart failure from the Department of Cardiology, St.
Olav’s Hospital, Trondheim, Norway. None of the patients had a
myocardial infarction in the 12 months preceding the study. Twelve
patients were ?80 years of age, 9 were 70 to 80 years old, 4 were 60
to 70 years old, and 2 were 50 to 60 years of age. All exhibited an
LV ejection fraction ?40% and were stable with optimal treatment
that included ?-blockers and angiotensin-converting enzyme (ACE)
inhibitors. All patients had received ?-blockers and ACE inhibitors
for ?12 months. One patient had atrial fibrillation; the rest had sinus
rhythm as evidenced by a-wave velocities. None of the patients had
a pacemaker. As judged by the body mass index (Table 1), patients
were noncachectic. Patients were randomly assigned to either high-
intensity AIT (n?9), MCT (n?9), or a control group (n?9).
Exclusion criteria included unstable angina pectoris, uncompensated
heart failure, myocardial infarction during the past 4 weeks, complex
ventricular arrhythmias, no use of ?-blockers and ACE inhibitors,
and orthopedic or neurological limitations to exercise. Medications
(Table 1) did not change during the 12-week study period. The study
was performed according to the Helsinki declaration and was
approved by the regional medical research ethics committee. Written
informed consent was obtained from all patients.
Randomization Procedure
Subjects were randomized and stratified (by gender and age) to AIT,
MCT, or control. The randomization code was developed with a
computer random-number generator to select random permuted
blocks.
Exercise Testing
After a 10-minute warm-up, a V˙O2peaktest (with MetaMax II, Cortex,
Leipzig, Germany) was performed with an individualized treadmill
ramp protocol with individualized constant band speed and increased
inclination by 2% when oxygen uptake stabilized at each workload
until V˙O2peakwas reached. A leveling off of oxygen uptake despite
increased workload and a respiratory exchange ratio ?1.05 were
used as criteria for maximal oxygen uptake. This was accomplished
in 25 of 27 patients (at pretest and posttest), and results are by
definition V˙O2peak. Work economy was determined as oxygen uptake
at a standard submaximal workload; for each patient, we used the
identical workload at posttest to measure work economy. Immedi-
ately after this workload, blood was drawn from a fingertip for
measurement of lactate concentration. Ventilatory threshold was
recorded as an indication of anaerobic threshold.
Exercise Training
Patients randomized to AIT and MCT met for supervised training
twice weekly and performed 1 weekly session at home. The control
group met for supervised training once every 3 weeks. All training
consisted of “uphill” treadmill walking as described previously.4The
AIT group warmed up for 10 minutes at 50% to 60% of V˙O2peak
(?60% to 70% of peak heart rate) before walking four 4-minute
intervals at 90% to 95% of peak heart rate. Each interval was
separated by 3-minute active pauses, walking at 50% to 70% of peak
heart rate. The training session was terminated by a 3-minute
cool-down at 50% to 70% of peak heart rate. Total exercise time was
38 minutes for the AIT group. Patients in the MCT group walked
continuously at 70% to 75% of peak heart rate for 47 minutes each
session to make sure the training protocols were isocaloric, as
detailed previously.4All subjects used a heart rate monitor (Polar
Electro, Kempele, Finland) to obtain the assigned exercise intensity.
The Borg 6-to-20 scale was used to assess the rate of perceived
exertion during and after each training session. The speed and
inclination of the treadmill was adjusted continuously to ensure that
every training session was carried out at the assigned heart rate
throughout the training period. Blood lactate was measured after the
first 3 and last 3 training sessions. Weekly home-based training
consisted of outdoor uphill walking. Patients were instructed to
perform the training program as in the laboratory; patients in the
MCT group walked continuously for 47 minutes without breathing
heavily, whereas AIT patients performed four 4-minute intervals
with an exercise intensity that made them breathe heavily without
becoming too stiff in their legs. Patients were instructed to immedi-
ately stop home-based training if they had chest pain or any other
distressing symptoms and contact the emergency department at the
hospital. Home-based training intensity was recorded twice by heart
TABLE 1. Patient Characteristics and Medication Use
Control MCTAIT
Male/female
Age, y
Body mass index, kg/m2
Systolic blood pressure, mm Hg
Diastolic blood pressure, mm Hg
Hemoglobin, g/dL
Total cholesterol, mmol/L
Serum creatinine, ?mol/L
ACE inhibitor
?-Blockers
Statins
Diuretics
Long-acting nitrates
Aspirin
Warfarin
Percutaneous coronary intervention*
Coronary artery bypass surgery*
6/37/27/2
75.5?13
25.5?2
121?7
76?11
15.2?1.3
5.9?1.5
118?56
9/9
9/9
9/9
5/9
4/9
3/9
6/9
2/9
74.4?12
24.7?3
124?11
73?8
14.4?1.1
5.4?1.2
126?42
9/9
9/9
9/9
4/9
5/9
3/9
6/9
2/9
1/9
76.5?9
24.5?3
119?9
72?10
14.9?1.1
5.5?1.2
108?20
9/9
9/9
9/9
5/9
4/9
4/9
5/9
1/9
? ? ?? ? ?
Data are mean?SD or number of patients.
*Intervention performed ?12 months ago.
Wisløff et al Interval Training in Heart Failure
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rate monitors, placed so that the patients were unable to see their
heart rate during the exercise. Recordings affirmed the correct
exercise intensity during home training. The control group was told
to follow advice from their family doctor with regard to physical
activity; in addition, they met for 47 minutes of continuous treadmill
walking at 70% of peak heart rate every 3 weeks.
Endothelial Function
Endothelium-dependent and endothelium-independent dilation of the
brachial artery was measured by ultrasound (14-MHz ultrasound
Doppler probe, Vivid 7 system, GE Vingmed Ultrasound, Horten,
Norway).11The guidelines for determining and analyzing flow-
mediated dilation (FMD) described by Corretti et al12were adhered
to strictly. The measurements were done on the brachial artery 4.5
cm above the antecubital fossa before inflation of a pneumatic cuff
on the upper arm to 250 mm Hg for 5 minutes and at 1 minute after
cuff release. FMD was expressed as percentage dilation from
baseline diameter to that observed 1 minute after cuff release.
Endothelium-independent dilation was measured by administering
500 ?g of nitroglycerin sublingually; no differences between groups
were observed (data not shown).
Echocardiography
Echocardiography was performed by 2 experienced cardiologists
(A.S. and T.S.) blinded to the patients’ group assignment. Subjects
were examined at rest in the left lateral supine position with a
Vingmed Vivid 7 scanner with B-mode ultrasound at a frame rate of
50 Hz. The following data were recorded: parasternal M-mode and
long-axis B-mode; apical B-mode from 3 standard planes; pulsed
Doppler flow recordings of LV outflow, mitral inflow, and apical
M-mode; and pulsed tissue Doppler in the septal and lateral points in
the 4-chamber plane and the anterior and posterior points in the
2-chamber plane. Systolic mitral annulus excursion and peak annulus
velocities in systole, early diastole (Ea), and late diastole were
measured as the average of the 4 points. Volumes were measured by
the modified Simpson biplane method. Stroke volume was measured
by 2D volumetry.
Muscle Biopsy
Muscle biopsy samples were obtained from the vastus lateralis with
a sterile 5-mm-diameter biopsy needle (Bergstrom) under local
anesthesia. Muscle biopsy samples were homogenized in lysis
buffer, and equal amounts of lysates were analyzed by SDS-PAGE
and Western blot analysis with goat polyclonal antibodies against
peroxisome proliferative activated receptor-? coactivator-1? (PGC-
1?), an indicator of mitochondrial biogenesis (Santa Cruz Biotech-
nology, Santa Cruz, Calif). Gels were reprobed with a monoclonal
antibody against ?-actin for normalization (Sigma, St. Louis, Mo).
Proteins were detected by chemiluminescence and quantified by
densitometry.
Sarcoplasmic Reticulum Ca2?ATPase-1 and -2
Transport Measurements
Reduced maximal rate of calcium (Ca2?) reuptake into sarcoplas-
matic reticulum has been inversely related to increased skeletal
muscle fatigue in heart failure patients. To measure this, Ca2?(50
?mol/L) was added to skinned fibers from the vastus lateralis muscle
to induce a rapid increase in [Ca2?], and kinetics of the subsequent
decline in Ca2?were analyzed with Fura-2 and an epifluorescence
microscope (Diaphot-TMD, Nikon, Tokyo, Japan) to assess maxi-
mum sarcoplasmic reticulum Ca2?ATPase (SERCA)-1 and -2
transport capacity.
Blood Analyses
Citrated and EDTA plasma was obtained from venous blood by
centrifugation at 3000 rpm for 10 minutes at 4°C. Aliquots of plasma
were then stored at ?80°C to allow batch analysis.
Serum triglycerides, glucose, high-density lipoprotein, low-
density lipoprotein (LDL), total cholesterol, hemoglobin, high-
sensitivity serum C-reactive protein, and creatinine were measured
with standard procedures at St. Olav’s University Hospital, Trond-
heim, Norway. Oxidized LDL was measured in plasma with the
Mercodia oxidized-LDL ELISA (Mercodia, Uppsala, Sweden). Total
antioxidant status (TAS) was measured in plasma samples with the
colorimetric TAS assay (Randox Laboratories Ltd, Crumlin, United
Kingdom). The method is
ethylbenzthiazoline-6-sulfonic acid) (ABTS) incubation with met-
myoglobin and H2O2to produce the radical cation ABTS?. The
radical has a stable blue-green color that is measured at 600 nm.
Antioxidants present in the added sample weaken the color intensity
in proportion to their concentration. The assay was performed with
an automated system (Cobas Mira Analyzer, Hoffmann-LaRoche,
Basel, Switzerland). For calculation of total antioxidant status, the
absorbance of the patient’s plasma was related to the standard,
6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox,
1.76 mmol/L), according to the manufacturer’s instructions (Randox
Laboratories Ltd, Crumlin, UK). Commercial enzyme immunoas-
says were used to determine endothelin-1 (R&D Systems, Minneap-
olis, Minn), insulin-like growth factor 1 (R&D Systems), and
pro-B-type natriuretic peptide levels (proBNP, Roche Diagnostics,
Indianapolis, Ind).
basedon2,2?-azino-bis-(3-
Quality of Life
Quality of life was measured by the MacNew Heart Disease
Health-Related Quality of Life questionnaire (MacNew),13which
has been shown to be well-suited for an older population. The
self-administered MacNew questionnaire is designed to evaluate
how daily activities and physical, emotional, and social functioning
are affected by heart disease.13
Statistical Analysis
Data are expressed as mean?SD unless otherwise stated, with a
significance level of P?0.05. The Kruskal-Wallis test and post hoc
test was used to evaluate unrelated observations between groups,
whereas ANOVA with Scheffé post hoc analysis determined group
differences between related observations.
The authors had full access to and take full responsibility for the
integrity of the data. All authors have read and agree to the
manuscript as written.
Results
At baseline, there were no differences in medical treatment
(Table 1) or physiological variables (Tables 2 through 4)
among the 3 groups. Medical treatment did not change during
the intervention period. During the experimental period, 1 of
the patients in the moderate-intensity group died of cardiac
causes, unrelated to exercise training, and data from 26
patients were available from postexercise tests. Patients in the
AIT and MCT groups performed 92?2% and 95?3% of the
scheduled training sessions, respectively. Measured exercise
intensity, blood lactate, and Borg scale were different be-
tween the AIT and MCT groups during the training sessions,
which confirms that the difference in exercise intensity
between the groups was as intended (Table 2).
Clinical Follow-Up
Body mass index, blood pressure, hemoglobin, total cholesterol,
and serum creatinine did not change (baseline values presented
in Table 1). AIT subjects tended to have lower serum triglycer-
ide (2.1?1.2 mmol/L pretest versus 1.7?0.7 mmol/L posttest,
P?0.11) and fasting glucose (7.0?2.0 mmol/L pretest versus
6.1?2.6 mmol/L posttest, P?0.10) levels after training, in
addition to a trend for increased high-density lipoprotein levels
(1.2?0.4 versus 1.3?0.3 mmol/L, P?0.20). The New York
Heart Association functional class tended to be reduced in both
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training groups (P?0.21) and was 2.5?0.5 for all subjects
combined at follow-up. No adverse effects of exercise training
were detected.
Exercise Capacity
After 12 weeks of exercise training, V˙O2peakincreased 46%
and 14% in the AIT and MCT groups, respectively
(P?0.001; Table 2; Figure 1). Anaerobic threshold increased
more in relative terms (percent of V˙O2peak) but not in absolute
terms (mL · kg?1· min?1, and workload) in MCT compared
with AIT (Table 2). AIT improved work economy as dem-
onstrated by 15% reduced oxygen cost, an 8-bpm lower heart
rate, and 59% lower blood lactate at a given submaximal
walking speed (Table 2). To extend the clinical usefulness of
exercise training for those without access to heart rate
monitors, patients were asked to indicate the level of effort
during exercise on a Borg scale (Table 2), and a Borg scale
score of 17?1 and 12?1 for AIT and MCT, respectively, was
reported.
PGC-1? and SERCA: Skeletal Muscle Molecular
Mechanisms of Exercise Capacity
Protein levels of PGC-1?, a critical factor coordinating the
activation of metabolic genes required for substrate utilization
TABLE 3. LV Volumes and Resting Hemodynamics
Control MCTAIT
Baseline Follow-Up BaselineFollow-UpBaselineFollow-Up
LVDD, mm
LVSD, mm
LVEDV, mL
LVESV, mL
HR at rest, bpm
SV, mL
CO, L/min
EF, %
67.2?8.1
56.2?9.2
250.5?64.4
187.8?53.0
60?11
53.4?15.3
3.1?0.6
26.2?8.0
67.8?12.5
56.7?13.7
242.1?62.3
186.6?58.6
59?11
55.0?13.7
3.2?0.5
26.6?9.7
69.1?8.6
56.6?8.8
245.5?53.1
172.9?48.7
55?10
63.5?12.7
3.5?0.9
32.8?4.8
68.2?6.5
53.9?7.4
230.3?41.0
160.6?34.3
54?12
63.1?15.7
3.4?1.1
33.5?5.7
66.7?6.8
53.9?6.7
248.1?79.6
177.4?72.1
65?14
57.1?14.3
3.5?0.5
28.0?7.3
59.0?6.8*†
46.1?8.2*†
202.9?72.0*†
133.9?57.8*†
61?13
67.0?19.9*
3.9?0.6*
38.0?9.8*†
Data are mean?SD. LVDD indicates LV diastolic diameter; LVSD, LV systolic diameter; LVEDV, LV end-diastolic volume; LVESV, LV
end-systolic diameter; HR, heart rate; SV, stroke volume; CO, cardiac output; and EF, ejection fraction.
*Different from baseline, P?0.01; †different from controls and moderately trained, P?0.02.
TABLE 2.Aerobic Capacity and Exercise Data
ControlMCTAIT
Baseline Follow-UpBaseline Follow-UpBaselineFollow-Up
Peak treadmill test
V˙o2peak, mL ? kg?1? min?1
Peak heart rate, bpm
?La??bat V˙o2peak, mmol/L
RER at V˙o2peak
Anaerobic threshold
% Of peak oxygen uptake
mL ? kg?1? min?1
Work economy
mL ? kg?1? min?1
Heart rate, bpm
?La??b, mmol/L
Training data
Exercise intensity, km/h
Inclination of treadmill, %
?La??b, mmol/L
% Of peak heart rate
Borg scale
13.2?1.9
129?23
6.3?1.6
1.10?0.04
13.4?2.0
127?21
6.3?1.2
1.11?0.04
13.0?1.1
132?18
6.8?1.2
1.10?0.04
14.9?0.9*
130?21
6.4?1.0
1.09?0.05
13.0?1.6
129?19
6.2?0.8
1.08?0.05
19.0?2.1*†
127?22
6.0?0.6
1.11?0.04
64?6
8.5?1.6
65?4
8.7?3.9
61?3
8.0?0.7
68?4*‡
10.1?0.9*§
63?5
8.2?0.8
61?3
11.6?1.0*†
8.5?1.6
84?9
2.81?0.4
9.1?2.8
88?8
3.0?0.8
8.0?0.7
82?6
2.9?0.3
7.6?0.8§
81?9
2.5?0.4
8.2?0.8
84?9
2.7?0.3
7.0?0.6*†
76?5*†
1.6?0.4*†
3.3?1.0
2.3?1.5
2.4?0.3
71?2
12?1
3.3?1.0
2.3?1.5
2.6?0.9
69?3
12?1
3.0?0.8
2.3?0.6
2.3?0.4
74?2
12?1
4.0?0.5
4.7?1.5§
2.4?0.6
73?2
12?1
3.1?0.2
2.7?1.0
5.0?0.5†
92?2†
17?1†
4.6?0.6*†
12.1?1.8*†
5.2?0.5†
93?3†
17?1†
?La??bindicates blood lactate; RER, respiratory exchange ratio.
Data are mean?SD. Work economy was measured at the same speed/inclination for each individual before and after the
experimental period.
*Different from baseline, P?0.01; †different from control and MCT, P?0.05; ‡different from control and AIT, P?0.01; §significantly
different from control, P?0.05.
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and mitochondrial biogenesis,14was increased by 47% in AIT
subjects (P?0.01; Figure 2A) and correlated with improved
V˙O2peak(R?0.71, P?0.01). Maximal rate of Ca2?reuptake into
sarcoplasmatic reticulum by SERCA in skeletal muscles in-
creased by 60% (P?0.01; Figure 2B) with AIT and correlated
with the improvement in V˙O2peak(R?0.56, P?0.05).
LV Remodeling
Twelve weeks of AIT induced reverse LV remodeling. LV
diastolic and systolic diameters declined by 12% and 15%
and estimated LV end-diastolic and end-systolic volumes by
18% and 25%, respectively (Table 3). proBNP, a marker of
hypertrophy and severity of heart failure, declined by 40%
AIT
MCT
Control
-5
0
5
10
15
)
%
(
D
M
F
10
15
20
25
l
m ⋅ g
k
1
-⋅ g
k
1
-
-5
0
5
10
15
)
%
(
D
M
F
10
15
20
25
l
m ⋅ g
k
1
-⋅

n i
m
1
-
-5
0
5
10
15
)
%
(
D
M
F
10
15
20
25
l
m ⋅ g
k
1
-⋅

n i
m
1
-
Endothelial function
Maximal oxygen uptake
Baseline Follow-upBaseline Follow-up
NS
NS
P < 0.01
P < 0.01
P < 0.01
P < 0.001
§
†
†
§
Figure 1. Left, Endothelial function measured as
FMD. Right, Maximal oxygen uptake. Data are
mean?SD. Lines represent individual values. Proba-
bility values inside figures indicate within-group dif-
ferences. §Different from control and MCT, P?0.01;
†different from control, P?0.01.
TABLE 4.Echocardiographic Resting LV Function
ControlMCTAIT
BaselineFollow-Up BaselineFollow-Up BaselineFollow-Up
Systolic function
MAE, mm
Sa,
LVOTmax, cm/s
Diastolic function
IVRT, ms
E, m/s
A, m/s
E/A
Ea, cm/s
Aa, cm/s
E/Ea
8.0?2.1
4.73?1.23
78.7?16.1
8.1?2.5
4.79?1.34
77.6?9.7
8.8?1.8
4.80?1.10
78.7?9.1
8.6?2.0
5.16?0.96
78.1?7.3
7.4?2.4
4.79?1.32
81.8?11.5
9.6?2.8*‡
5.86?1.53*‡
97.7?10.5*‡
110.2?68.7
0.6?0.1
0.9?0.1
0.7?0.2
4.0?1.4
7.0?2.2
15.1?4.3
109.5?64.8
0.5?0.2
0.9?0.1
0.6?0.2
3.9?1.9
7.5?2.8
15.1?6.4
112.4?23.4
0.7?0.3
1.0?0.2
0.8?0.1
4.6?0.8
8.8?1.8
15.1?5.4
105.7?25.6
0.6?0.1†
0.7?0.2*
0.8?0.3
4.7?1.6
7.5?1.8
12.9?3.8†§
100.7?18.9
0.7?0.1
0.9?0.1
0.7?0.1
4.5?1.3
8.6?1.7
16.0?3.5
122.8?41.4†‡
0.8?0.2
0.9?0.3
0.9?0.2†§
6.7?1.6*‡
8.5?1.8
11.8?1.9*§
MAE indicates systolic mitral annulus excursion; Sa, peak mitral annulus velocity during systole by tissue Doppler; LVOTmax, peak
ejection velocity in LV outlet tract; IVRT, isovolumic relaxation time; E, peak mitral flow velocity during early filling; A, peak mitral flow
during atrial systole; Ea, peak annulus velocity during early filling; and Aa, peak annulus velocity during atrial systole.
*Different from baseline, P?0.01; †different from baseline, P?0.05; ‡different from controls and MCT, P?0.02; §different from
control, P?0.05.
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(P?0.02) with AIT (Figure 2C). Endurance training did not
influence wall thickness (data not shown).
Systolic Function
All indexes of LV systolic performance in the present study
suggest that AIT was highly effective in improving systolic
function: LV ejection fraction increased by 10 percentage
points, which corresponds to 35% in relative terms (P?0.01;
Table 3), the systolic mitral annulus excursion by 30%
(P?0.01; Table 4), and stroke volume by 17% (P?0.01;
Table 3). Furthermore, peak systolic mitral annulus velocity
measured by tissue Doppler imaging, which is an index of
global contractility,15increased by 22% (P?0.01; Table 4).
Peak ejection velocity, as measured by standard Doppler in
the LV outlet tract, was increased by 19% (P?0.05; Table 4).
No significant changes occurred in systolic function in the
MCT or control groups.
Diastolic Function
Ea is the most direct measure of ventricular relaxation and
appears to be less sensitive to alterations in preload than the
traditional Doppler E/A ratio. AIT, but not MCT, improved
Ea by 49% (P?0.01; Table 4) and the E/A ratio by 15%
(P?0.05; Table 4). The ratio of transmitral flow velocity (E)
versus annular velocity (Ea) has been proposed as the best
indicator to assess LV filling pressure. It combines the
influence of transmitral driving pressure and myocardial
relaxation and appears to be less sensitive to alterations in
preload than the standard Doppler E/A ratio. AIT and MCT
reduced E/Ea by 26% (P?0.001) and 15% (P?0.043; AIT
versus MCT, P?0.05; Table 4), respectively. Isovolumic
relaxation time increased by 22% (P?0.05) in AIT, but no
change was detected in the other groups (Table 4). Deceler-
ation time of the mitral flow E wave did not change
significantly in any of the groups.
Endothelial Function
Endothelial dysfunction contributes to exercise intolerance,
impaired myocardial perfusion, and LV remodeling in
chronic heart failure and serves as an independent prognostic
marker for future cardiovascular events (e.g.16). We observed
a close relationship between improved aerobic capacity and
improved FMD (R?0.69, P?0.05) and a greater improve-
ment in FMD by AIT than by MCT (P?0.05; Figure 1).
2
3
4
5
6
p < 0.01§
Control MCT AIT
NS
NS
1
-
C
G
P
α α α α/α α α α
n
i t c
A
-
) s
t i n
u
y
r
a
t i b
r
A
(
0
2
4
6
8
10
12
p < 0.01§
p = 0.17
Control MCT AIT
NS
a
C

R
S
f
o
e
t a
R
+
2

e
k
a
t
p
u
)
g
m
/ s / e l o
m
p
, x
a
m
V
(
A B
Baseline
Follow-up
500
1000
1500
2000
p < 0.02§
Control MCT AIT
NS
NS
)
L
m
/ g
p
(
P
N
B
o
r
p
E
C D
1.0
1.2
1.4
1.6
p = 0.02
p = 0.055NS
Control MCT AIT
s
u
t a
t s t
n
a
d
i x
o
i t
n
a l a
t
o
T
)
M
m
(
60
80
100
120
NS
NS
p = 0.03
Control MCT AIT
)
L
/
U
( L
D
L
d
e
z i d
i x
O
Figure 2. A, PGC-1? in vastus lateralis muscle.
B, Rate of maximal Ca2?reuptake (Vmax) in the
sarcoplasmic reticulum (SR) in permeabilized
samples of vastus lateralis muscle. C, Plasma
level of brain natriuretic peptide (proBNP). D,
Total antioxidant status in plasma, ie, the indi-
vidual’s level of protection against attack by
free oxygen radicals. Total antioxidant status
was related to the standard (Trolox 1.76 mmol/
L). E, Oxidized LDL in plasma. Data are
mean?SD. Probability values inside figures
represent within-group differences. §Different
from control and MCT groups, P?0.01.
Wisløff et alInterval Training in Heart Failure
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Central to the regulation of FMD is the bioavailability of
nitric oxide (NO), and abnormalities in 1 or more pathways
that ultimately regulate the availability of NO may lead to
endothelial dysfunction. It is well established that increased
oxidative stress and oxidized LDL reduce the bioavailability
of NO, and in the present study, we observed that AIT
patientsincreasedtheirantioxidative
(P?0.02), which indicates a lower level of reactive oxygen
species and higher NO production. In line with this, enhanced
FMD correlated with increased total antioxidant status in
blood plasma (R?0.67, P?0.01; Figure 2D). Furthermore,
AIT reduced the plasma levels of oxidized LDL by 9%
(Figure 2E; R?0.59, P?0.03).
Endurance training did not change the plasma levels of
insulin-like growth factor-1 or endothelin-1 (ET-1). After the
exercise test, the median values were 2.9 (95% CI, 2.4 to 3.5)
pg/mL and 61.3 (95% CI, 53.2 to 70.8) ng/mL, respectively.
Finally, high-sensitivity C-reactive protein was similar be-
tween groups and was not changed by endurance training.
The median high-sensitivity C-reactive protein value for all
groups combined was 5.6 (95% CI, 3.8 to 12.8) mg/L.
status by15%
Quality of Life
The MacNew global score for quality of life in cardiovascular
disease increased both after MCT (4.4?0.4 versus 5.2?0.2,
P?0.01) and after AIT (4.41?0.32 versus 5.73?0.19,
P?0.001; difference between groups P?0.02). No change
occurred in the control group (4.49?0.24 versus 4.48?0.36).
Discussion
The major finding of the present study was that AIT was
superior to MCT in patients with postinfarction heart failure
with regard to reversal of LV remodeling, aerobic capacity,
endothelial function, and quality of life. Of particular interest
is the old age of the majority of patients in the present study,
who demonstrated robust training-induced adaptation, even in
elderly heart failure patients. This is important information
because chronic heart failure is a disease of the elderly; in
fact, it has been reported that 88% and 49% of patients with
a first diagnosis of chronic heart failure were ?65 and ?80
years old, respectively.17Despite this, most previous studies
have excluded patients with an age ?70 years.
Aerobic Capacity
The large increase in V˙O2peakin AIT may be explained in part
by lower baseline values and a higher exercise intensity than
in previous studies (eg, Dubach et al18and Gielen et al19), and
one could speculate whether we underestimated V˙O2peak at
before exercise but not afterward. However, this appears
unlikely, because only 2 patients did not manage to satisfy the
criteria defined for reaching true maximal oxygen uptake at
both time points. Furthermore, high blood lactate concentra-
tions and high respiratory exchange ratios suggest that the
patients exercised at maximum effort at both occasions.
Two previous studies20,21involving patients with coronary
artery disease have employed aerobic interval exercise with
elements of the same high intensity as in the present study,
both with a substantial increase of V˙O2peak. These studies
showed that 12 months of exercise at 50% to 95% of V˙O2peak
3 to 5 times per week induced an improvement in V˙O2peakof
37% to 42%. A longer training period, a large variation in
exercise intensity, and varying numbers of training sessions
per week makes comparison with the present study difficult;
however, the previous studies demonstrated that high exercise
intensity is associated with a large improvement of V˙O2peak.
The main goal of the present study was to evaluate the effect
of exercise when intensity was the only independent variable.
The high-intensity exercise was chosen to be aerobic interval
exercise at 90% to 95% of peak heart rate because this
training method has been used by our research group in
healthy individuals, yielding large improvements in V˙O2peak
within a relatively short time period.22Informal comments
from the patients in the exercise groups indicated that patients
in the AIT group found it motivating to have a varied
procedure to follow during each training, whereas those in the
MCT group found it “quite boring” to walk continuously
during the entire exercise period. In addition to improved
V˙O2peak, improved anaerobic threshold and work economy
increase the patient’s ability to cope with the physical
demands of daily activity.23The present study demonstrated
that the anaerobic threshold increased more in AIT than MCT
when expressed in absolute workloads. Interestingly, AIT but
not MCT improved the patients’ work economy (Table 2).
The reason for these adaptations is not fully understood but
probably reflects improved mitochondrial function (as indi-
cated by an increased level of PGC-1?) and calcium cycling
in skeletal muscle of AIT patients (as suggested by increased
SERCA capacity).
Reversed LV Remodeling
Lower plasma proBNP levels clearly demonstrate the effec-
tiveness of AIT in modifying postinfarction remodeling.
Accordingly, AIT reduced LV end-diastolic and end-systolic
volumes by 18% and 25%, respectively, similar to the effect
of 3 months of cardiac resynchronization therapy.24It has
been shown that treatment with ACE inhibitors halts the
progression of remodeling,25whereas combined treatment
with ACE inhibitors and ?-blockers in patients with chronic
heart failure increases ejection fraction ?12%26similar to the
findings with AIT in the present study. These observations
indicate that AIT utilizes a potential for further reversal of
remodeling, because it was added on top of medication.
Moreover, myocardial contractile function also markedly
improved in AIT patients in terms of ejection fraction, stroke
volume, mitral annular excursion, ejection velocity, and
systolic mitral annular velocity measured by tissue Doppler
imaging.
Ea, which is the most direct measure of LV relaxation and
is less sensitive to load than flow indices,27was improved in
the AIT group only. Mitral flow is a function of both left
atrial pressure and LV relaxation, and the ratio of transmitral
flow velocity (E) versus annular velocity (Ea) has been
proposed as an indicator of LV filling pressure.28E/Ea
decreased substantially in the AIT group, which indicates a
decrease in filling pressure toward normal. This is consistent
with the increase in isovolumic relaxation time. MCT had no
significant effect on LV systolic or diastolic performance,
measured by tissue Doppler imaging, other than causing a
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minor improvement in the E/Ea ratio; however, the decreased
E/Ea ratio in MCT was due to a small decrease in transmitral
flow velocity alone and was not accompanied by supporting
evidence showing an increase in E/A or isovolumic relaxation
time, and it might, therefore, represent a dubious result.
Endothelial Function
It is well established that endurance training improves coro-
nary endothelium-dependent vasodilation in patients with
coronary artery disease.29It is therefore reasonable to spec-
ulate that this also occurred in the present study and contrib-
uted to the antiremodeling effect of AIT in the LV.
Both the level of reactive oxygen species and the amount
of oxidized LDL are known to directly influence NO bio-
availability, and a normal endothelial function is dependent
on the balance of oxidant and antioxidant mechanisms.
During oxidative stress, superoxide anions (O2
function of endothelial NO synthase and reduce the half-life
of NO by increasing the production of peroxynitrite from NO
and O2
superoxide dismutase. AIT improved FMD more than MCT,
and the reason for this may be the increased bioavailability of
NO in AIT patients. In line with this notion, we found that
AIT increased the antioxidant status in blood plasma, which
indicates reduced oxidative stress. These results are in agree-
ment with a recent study by Linke et al30demonstrating
antioxidative effects of exercise training in skeletal muscle of
patents with chronic heart failure. Because AIT reduced the
amount of reactive oxygen species, it was not surprising that
oxidized LDL was lower in AIT. Why AIT was more
effective is unknown, but it appears reasonable to speculate
that higher shear stress during the exercise bouts of AIT
patients triggers larger responses at the cellular and molecular
level. Despite the decreased level of reactive oxygen species
and improved NO-mediated endothelial function, we did not
observe any change in the levels of endothelin-1 and insulin-
like growth factor-1 in blood, which indicates that endurance
training acts through other pathways or may act locally to
improve endothelial function.
?) decrease the
?, whereas in the normal state, the O2
?is quenched by
Quality of Life
The physiological improvements were paralleled by better
quality of life. Interestingly, quality of life improved more
markedly in AIT subjects than in the other groups, which
suggests that more intensive physical training is more reward-
ing. This observation is in line with a study by Klocek et al.31
The mechanism of the superior effect of intensive physical
training on the quality of life is not presently known, but it is
reasonable to suggest that it is due to greater physiological
adaptation and thereby improved capacity for activity in AIT
subjects.
Study Limitations
The number of patients in the present study was small, and
subjects were predominantly males, which precludes any
inference about the safety of this training technique. The
study should therefore be regarded as a “proof-of-concept”
study. It is not known whether the present training protocol
will yield similar adaptations in heart failure due to causes
other than myocardial infarction. A recent study by Rognmo
et al4showed that a similar interval program was more than
twice as effective in improving V˙O2peak compared with
moderate-intensity exercise in patients with coronary artery
disease. However, the present data are provocative and
should encourage the creation of larger multicenter studies
using the same training technique and addressing the safety
issue.
Conclusions
The present study demonstrates that high-intensity training
relative to the individual’s maximal oxygen uptake is feasible
even in elderly patients with chronic heart failure and
severely impaired cardiovascular function. It also shows that
the intensity of exercise may be an important factor for
reversing LV remodeling, improving aerobic capacity, and
improving quality of life in patients with postinfarction heart
failure. These findings may have important implications for
exercise training in rehabilitation programs and future stud-
ies. It is our view that the time has come to perform
multicenter studies comparing exercise at moderate versus
high relative intensities for stable cardiovascular patients,
including those with postinfarction heart failure. We suggest
that training programs based on these principles may yield
more favorable results than those with low to moderate
exercise intensities.
Acknowledgments
We acknowledge assistance from professor Geir A. Espnes and
professor Neil Oldridge regarding the literature on quality-of-life
measures.
Sources of Funding
The present study was supported by grants from the Norwegian
Council of Cardiovascular Disease, Foundations for Cardiovascular
and Medical Research at St. Olav’s University Hospital, Trondheim,
and Torstein Erbo’s foundation, Trondheim. This work was also
supported by grants from the National Institutes of Health (DK
54254), the American Diabetes Association, and the United States
Department of Agriculture (USDA 2005-38903-02315). The funding
organizations had no role in the design and conduct of the study; in
the collection, analysis, and interpretation of the data; or in the
preparation, review, or approval of the manuscript.
Disclosures
None.
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31. Klocek M, Kubinyi A, Bacior B, Kawecka-Jaszcz K. Effect of physical
training on quality of life and oxygen consumption in patients with
congestive heart failure. Int J Cardiol. 2005;103:323–329.
CLINICAL PERSPECTIVE
In recent years, there has been a growing consensus that physical inactivity accelerates the severity of heart failure and that
the level of aerobic fitness predicts survival in a cardiovascular disease population, even when other traditional risk factors
are present or in the setting of established ?-blockade. However, there is still controversy regarding the level and format
of exercise that can yield optimal beneficial effects. In the present study, we sought to find out whether exercise intensity
was of importance for improving aerobic fitness and cardiac function in patients with postinfarction heart failure. Patients
aged 75.5?11.1 years either performed high-intensity aerobic interval training or moderate continuous exercise or received
standard advice regarding physical activity. The protocols were made isocaloric so that only exercise intensity differed
between the 2 intervention groups. The present study demonstrates that high-intensity training relative to the individual’s
aerobic fitness capacity is feasible even in elderly patients with chronic heart failure who have severely impaired
cardiovascular function. It also shows that the intensity of exercise is an important factor for reversing left ventricular
remodeling, improving aerobic capacity, and improving quality of life in patients with postinfarction heart failure.
3094Circulation
June 19, 2007
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