Hokksund-rehab.no

Superior Cardiovascular Effect of Aerobic Interval
Training Versus Moderate Continuous Training in Heart
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 yearsold, respectively. Despite this, most previous studies have excluded patients with an age ⬎70 years. Our objective wasto compare training programs with moderate versus high exercise intensity with regard to variables associated withcardiovascular 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; leftventricular [LV] ejection fraction 29%; V ˙ O2peak 13 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 increased more with aerobic interval training than moderate continuous training (46% versus 14%, P⬍0.001) and wasassociated with reverse LV remodeling. LV end-diastolic and end-systolic volumes declined with aerobic intervaltraining only, by 18% and 25%, respectively; LV ejection fraction increased 35%, and pro-brain natriuretic peptidedecreased 40%. Improvement in brachial artery flow-mediated dilation (endothelial function) was greater with aerobicinterval training, and mitochondrial function in lateral vastus muscle increased with aerobic interval training only. TheMacNew global score for quality of life in cardiovascular disease increased in both exercise groups. No changesoccurred 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:&NA;-.)
Key Words: endothelium 䡲 exercise 䡲 remodeling 䡲 heart failure
In recent years, there has been a growing consensus that Editorial p
exercise has beneficial effects in patients with cardiovas- Clinical Perspective p
cular disease, even for those with severely impaired cardiacfunction, and that physical inactivity accelerates the severity deaths among patients with established cardiovascular dis- of heart failure.1,2 Peak aerobic exercise capacity directly ease1,2; however, there is still controversy regarding the level measured as peak oxygen uptake (V and format of exercise that can yield optimal beneficial 2peak) was recently found to be the single best predictor of both cardiac and all-cause effects.3 Several 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 ofCardiology (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, Metabolismand 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 [email protected] 2007 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.org

June 19, 2007
cardiovascular adaptations after high-intensity exercise than Patient Characteristics and Medication Use
with low and moderate levels in patients with coronary artery disease,4 chronic heart failure,5,6 or left ventricular (LV) dysfunction function7 and in healthy subjects.8 Exercisetraining at an intensity of ⬇90% of V O2peak is in the upper range of current guidelines for humans.3 This level of aerobic Body mass index, kg/m2 exercise can be achieved in an interval-training format in both Systolic blood pressure, mm Hg humans and animal models. The rationale for interval training Diastolic blood pressure, mm Hg is that it allows for rest periods that make it possible for patients with heart failure to complete short work periods at Total cholesterol, mmol/L a higher intensity (which challenges the heart's pumping Serum creatinine, ␮mol/L ability) than would be possible during continuous exercise.
Aerobic interval training (AIT) involving periods at 90% ofV O2peak has 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.9 The beneficial effects Long-acting nitrates on cardiac remodeling and myocyte function were similar to those observed with the angiotensin II receptor blocker losartan,10 which indicates that AIT might be a potent Percutaneous coronary intervention* modifier of postinfarction heart failure. We therefore hypoth- Coronary artery bypass surgery* esized that AIT is more effective than moderate continuous training (MCT) in enhancing cardiovascular fitness and Data are mean⫾SD or number of patients.
*Intervention performed ⬎12 months ago.
reversing myocardial remodeling in patients undergoing op-timal treatment for stable heart failure after a myocardial increased workload and a respiratory exchange ratio ⬎1.05 were used as criteria for maximal oxygen uptake. This was accomplishedin 25 of 27 patients (at pretest and posttest), and results are by . Work economy was determined as oxygen uptake at a standard submaximal workload; for each patient, we used theidentical workload at posttest to measure work economy. Immedi- We enrolled 27 consecutive patients (aged 75.5⫾11.1 years) with ately after this workload, blood was drawn from a fingertip for postinfarction heart failure from the Department of Cardiology, St.
measurement of lactate concentration. Ventilatory threshold was Olav's Hospital, Trondheim, Norway. None of the patients had a recorded as an indication of anaerobic threshold.
myocardial infarction in the 12 months preceding the study. Twelvepatients 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 anLV ejection fraction ⬍40% and were stable with optimal treatment Patients randomized to AIT and MCT met for supervised training that included ␤-blockers and angiotensin-converting enzyme (ACE) twice weekly and performed 1 weekly session at home. The controlgroup met for supervised training once every 3 weeks. All training inhibitors. All patients had received ␤-blockers and ACE inhibitors consisted of "uphill" treadmill walking as described previously.4 The for ⬎12 months. One patient had atrial fibrillation; the rest had sinus AIT group warmed up for 10 minutes at 50% to 60% of V rhythm as evidenced by a-wave velocities. None of the patients had (⬇60% to 70% of peak heart rate) before walking four 4-minute a pacemaker. As judged by the body mass index (Table 1), patients intervals at 90% to 95% of peak heart rate. Each interval was were noncachectic. Patients were randomly assigned to either high- separated by 3-minute active pauses, walking at 50% to 70% of peak intensity AIT (n⫽9), MCT (n⫽9), or a control group (n⫽9).
heart rate. The training session was terminated by a 3-minute Exclusion criteria included unstable angina pectoris, uncompensated cool-down at 50% to 70% of peak heart rate. Total exercise time was heart failure, myocardial infarction during the past 4 weeks, complex 38 minutes for the AIT group. Patients in the MCT group walked ventricular arrhythmias, no use of ␤-blockers and ACE inhibitors, continuously at 70% to 75% of peak heart rate for 47 minutes each and orthopedic or neurological limitations to exercise. Medications session to make sure the training protocols were isocaloric, as (Table 1) did not change during the 12-week study period. The study detailed previously.4 All subjects used a heart rate monitor (Polar was performed according to the Helsinki declaration and was Electro, Kempele, Finland) to obtain the assigned exercise intensity.
approved by the regional medical research ethics committee. Written The Borg 6-to-20 scale was used to assess the rate of perceived informed consent was obtained from all patients.
exertion during and after each training session. The speed andinclination of the treadmill was adjusted continuously to ensure that every training session was carried out at the assigned heart rate Subjects were randomized and stratified (by gender and age) to AIT, throughout the training period. Blood lactate was measured after the MCT, or control. The randomization code was developed with a first 3 and last 3 training sessions. Weekly home-based training computer random-number generator to select random permuted consisted of outdoor uphill walking. Patients were instructed to perform the training program as in the laboratory; patients in theMCT group walked continuously for 47 minutes without breathing heavily, whereas AIT patients performed four 4-minute intervals After a 10-minute warm-up, a V test (with MetaMax II, Cortex, with an exercise intensity that made them breathe heavily without Leipzig, Germany) was performed with an individualized treadmill becoming too stiff in their legs. Patients were instructed to immedi- ramp protocol with individualized constant band speed and increased ately stop home-based training if they had chest pain or any other inclination by 2% when oxygen uptake stabilized at each workload distressing symptoms and contact the emergency department at the was reached. A leveling off of oxygen uptake despite hospital. Home-based training intensity was recorded twice by heart

Wisløff et al
Interval Training in Heart Failure
rate monitors, placed so that the patients were unable to see their with standard procedures at St. Olav's University Hospital, Trond- heart rate during the exercise. Recordings affirmed the correct heim, Norway. Oxidized LDL was measured in plasma with the exercise intensity during home training. The control group was told Mercodia oxidized-LDL ELISA (Mercodia, Uppsala, Sweden). Total to follow advice from their family doctor with regard to physical antioxidant status (TAS) was measured in plasma samples with the activity; in addition, they met for 47 minutes of continuous treadmill colorimetric TAS assay (Randox Laboratories Ltd, Crumlin, United walking at 70% of peak heart rate every 3 weeks.
ethylbenzthiazoline-6-sulfonic acid) (ABTS) incubation with met- myoglobin and H O to produce the radical cation ABTS⫹. The Endothelium-dependent and endothelium-independent dilation of the radical has a stable blue-green color that is measured at 600 nm.
brachial artery was measured by ultrasound (14-MHz ultrasound Antioxidants present in the added sample weaken the color intensity Doppler probe, Vivid 7 system, GE Vingmed Ultrasound, Horten, in proportion to their concentration. The assay was performed with Norway).11 The guidelines for determining and analyzing flow- an automated system (Cobas Mira Analyzer, Hoffmann-LaRoche, mediated dilation (FMD) described by Corretti et al12 were adhered Basel, Switzerland). For calculation of total antioxidant status, the to strictly. The measurements were done on the brachial artery 4.5 absorbance of the patient's plasma was related to the standard, 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 1.76 mmol/L), according to the manufacturer's instructions (Randox cuff release. FMD was expressed as percentage dilation from Laboratories Ltd, Crumlin, UK). Commercial enzyme immunoas- baseline diameter to that observed 1 minute after cuff release.
says were used to determine endothelin-1 (R&D Systems, Minneap- Endothelium-independent dilation was measured by administering olis, Minn), insulin-like growth factor 1 (R&D Systems), and 500 ␮g of nitroglycerin sublingually; no differences between groups pro-B-type natriuretic peptide levels (proBNP, Roche Diagnostics, were observed (data not shown).
Indianapolis, Ind).
Quality of Life
Echocardiography was performed by 2 experienced cardiologists Quality of life was measured by the MacNew Heart Disease (A.S. and T.S.) blinded to the patients' group assignment. Subjects Health-Related Quality of Life questionnaire (MacNew),13 which were examined at rest in the left lateral supine position with a has been shown to be well-suited for an older population. The Vingmed Vivid 7 scanner with B-mode ultrasound at a frame rate of self-administered MacNew questionnaire is designed to evaluate 50 Hz. The following data were recorded: parasternal M-mode and how daily activities and physical, emotional, and social functioning long-axis B-mode; apical B-mode from 3 standard planes; pulsed are affected by heart disease.13 Doppler flow recordings of LV outflow, mitral inflow, and apicalM-mode; and pulsed tissue Doppler in the septal and lateral points in the 4-chamber plane and the anterior and posterior points in the Data are expressed as mean⫾SD unless otherwise stated, with a 2-chamber plane. Systolic mitral annulus excursion and peak annulus significance level of P⬍0.05. The Kruskal-Wallis test and post hoc velocities in systole, early diastole (Ea), and late diastole were test was used to evaluate unrelated observations between groups, measured as the average of the 4 points. Volumes were measured by whereas ANOVA with Scheffé post hoc analysis determined group the modified Simpson biplane method. Stroke volume was measured differences between related observations.
by 2D volumetry.
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.
Muscle biopsy samples were obtained from the vastus lateralis witha sterile 5-mm-diameter biopsy needle (Bergstrom) under local anesthesia. Muscle biopsy samples were homogenized in lysisbuffer, and equal amounts of lysates were analyzed by SDS-PAGE At baseline, there were no differences in medical treatment and Western blot analysis with goat polyclonal antibodies against (Table 1) or physiological variables (Tables 2 through 4) peroxisome proliferative activated receptor-␥ coactivator-1␣ (PGC- among the 3 groups. Medical treatment did not change during 1␣), an indicator of mitochondrial biogenesis (Santa Cruz Biotech- the intervention period. During the experimental period, 1 of nology, Santa Cruz, Calif). Gels were reprobed with a monoclonalantibody against ␣-actin for normalization (Sigma, St. Louis, Mo).
the patients in the moderate-intensity group died of cardiac Proteins were detected by chemiluminescence and quantified by causes, unrelated to exercise training, and data from 26 patients were available from postexercise tests. Patients in theAIT and MCT groups performed 92⫾2% and 95⫾3% of the Sarcoplasmic Reticulum Ca2ⴙ ATPase-1 and -2
scheduled training sessions, respectively. Measured exercise intensity, blood lactate, and Borg scale were different be- Reduced maximal rate of calcium (Ca2⫹) reuptake into sarcoplas- tween the AIT and MCT groups during the training sessions, matic reticulum has been inversely related to increased skeletalmuscle fatigue in heart failure patients. To measure this, Ca2⫹ (50 which confirms that the difference in exercise intensity ␮mol/L) was added to skinned fibers from the vastus lateralis muscle between the groups was as intended (Table 2).
to induce a rapid increase in [Ca2⫹], and kinetics of the subsequentdecline in Ca2⫹ were analyzed with Fura-2 and an epifluorescence microscope (Diaphot-TMD, Nikon, Tokyo, Japan) to assess maxi- Body mass index, blood pressure, hemoglobin, total cholesterol, mum sarcoplasmic reticulum Ca2⫹ ATPase (SERCA)-1 and -2transport capacity.
and serum creatinine did not change (baseline values presentedin 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, Citrated and EDTA plasma was obtained from venous blood by P⫽0.11) and fasting glucose (7.0⫾2.0 mmol/L pretest versus centrifugation at 3000 rpm for 10 minutes at 4°C. Aliquots of plasma 6.1⫾2.6 mmol/L posttest, P⫽0.10) levels after training, in were then stored at ⫺80°C to allow batch analysis.
addition to a trend for increased high-density lipoprotein levels Serum triglycerides, glucose, high-density lipoprotein, low- density lipoprotein (LDL), total cholesterol, hemoglobin, high- (1.2⫾0.4 versus 1.3⫾0.3 mmol/L, P⫽0.20). The New York sensitivity serum C-reactive protein, and creatinine were measured Heart Association functional class tended to be reduced in both

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Aerobic Capacity and Exercise Data
Peak treadmill test V˙o2peak, mL 䡠 kg⫺1 䡠 min⫺1 Peak heart rate, bpm 关La⫺兴b at V˙o2peak, mmol/L Anaerobic threshold % Of peak oxygen uptake mL 䡠 kg⫺1 䡠 min⫺1 mL 䡠 kg⫺1 䡠 min⫺1 关La⫺兴b, mmol/L Exercise intensity, km/h Inclination of treadmill, % 关La⫺兴b, mmol/L % Of peak heart rate 关La⫺兴b indicates 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 *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.
training groups (P⫽0.21) and was 2.5⫾0.5 for all subjects rate, and 59% lower blood lactate at a given submaximal combined at follow-up. No adverse effects of exercise training walking speed (Table 2). To extend the clinical usefulness of were detected.
exercise training for those without access to heart ratemonitors, patients were asked to indicate the level of effort during exercise on a Borg scale (Table 2), and a Borg scale After 12 weeks of exercise training, V ˙ O2peak increased 46% score of 17⫾1 and 12⫾1 for AIT and MCT, respectively, was and 14% in the AIT and MCT groups, respectively (P⬍0.001; Table 2; Figure 1). Anaerobic threshold increasedmore in relative terms (percent of V ˙ O2peak) but not in absolute PGC-1␣ and SERCA: Skeletal Muscle Molecular
terms (mL · kg⫺1 · min⫺1, and workload) in MCT compared Mechanisms of Exercise Capacity
with AIT (Table 2). AIT improved work economy as dem- Protein levels of PGC-1␣, a critical factor coordinating the onstrated by 15% reduced oxygen cost, an 8-bpm lower heart activation of metabolic genes required for substrate utilization LV Volumes and Resting Hemodynamics
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.

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Interval Training in Heart Failure
Echocardiographic Resting LV Function
Systolic function Diastolic function 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 flowduring 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 and mitochondrial biogenesis,14 was increased by 47% in AIT subjects (P⬍0.01; Figure 2A) and correlated with improved Twelve weeks of AIT induced reverse LV remodeling. LV ˙ O2peak (R⫽0.71, P⬍0.01). Maximal rate of Ca2⫹ reuptake into diastolic and systolic diameters declined by 12% and 15% sarcoplasmatic reticulum by SERCA in skeletal muscles in- and estimated LV end-diastolic and end-systolic volumes by creased by 60% (P⬍0.01; Figure 2B) with AIT and correlated 18% and 25%, respectively (Table 3). proBNP, a marker of with the improvement in V ˙ O2peak (R⫽0.56, P⬍0.05).
hypertrophy and severity of heart failure, declined by 40% Maximal oxygen uptake
Figure 1. Left, Endothelial function measured as
P < 0.01
FMD. Right, Maximal oxygen uptake. Data are mean⫾SD. Lines represent individual values. Proba- P < 0.01
bility values inside figures indicate within-group dif- ferences. §Different from control and MCT, P⬍0.01; †different from control, P⬍0.01.
P < 0.001
P < 0.01
Follow-up

June 19, 2007
p < 0.01 §
p < 0.01 §
Control MCT AIT
Control MCT AIT
Figure 2. A, PGC-1␣ in vastus lateralis muscle.
B, Rate of maximal Ca2⫹ reuptake (Vmax) in the
sarcoplasmic reticulum (SR) in permeabilizedsamples 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 p < 0.02 §
mean⫾SD. Probability values inside figures represent within-group differences. §Different from control and MCT groups, P⬍0.01.
Control MCT AIT
Control MCT AIT
L
D
L dezi 80
Control MCT AIT
(P⬍0.02) with AIT (Figure 2C). Endurance training did not Ea by 49% (P⬍0.01; Table 4) and the E/A ratio by 15% influence wall thickness (data not shown).
(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 All indexes of LV systolic performance in the present study influence of transmitral driving pressure and myocardial suggest that AIT was highly effective in improving systolic relaxation and appears to be less sensitive to alterations in function: LV ejection fraction increased by 10 percentage preload than the standard Doppler E/A ratio. AIT and MCT points, which corresponds to 35% in relative terms (P⬍0.01; reduced E/Ea by 26% (P⫽0.001) and 15% (P⫽0.043; AIT Table 3), the systolic mitral annulus excursion by 30% versus MCT, P⬍0.05; Table 4), respectively. Isovolumic (P⬍0.01; Table 4), and stroke volume by 17% (P⬍0.01; relaxation time increased by 22% (P⬍0.05) in AIT, but no Table 3). Furthermore, peak systolic mitral annulus velocity change was detected in the other groups (Table 4). Deceler- measured by tissue Doppler imaging, which is an index of ation time of the mitral flow E wave did not change global contractility,15 increased by 22% (P⬍0.01; Table 4).
significantly in any of the groups.
Peak ejection velocity, as measured by standard Doppler inthe LV outlet tract, was increased by 19% (P⬍0.05; Table 4).
No significant changes occurred in systolic function in the Endothelial dysfunction contributes to exercise intolerance, MCT or control groups.
impaired myocardial perfusion, and LV remodeling inchronic heart failure and serves as an independent prognostic marker for future cardiovascular events (e.g.16). We observed Ea is the most direct measure of ventricular relaxation and a close relationship between improved aerobic capacity and appears to be less sensitive to alterations in preload than the improved FMD (R⫽0.69, P⬍0.05) and a greater improve- traditional Doppler E/A ratio. AIT, but not MCT, improved ment in FMD by AIT than by MCT (P⬍0.05; Figure 1).

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Interval Training in Heart Failure
Central to the regulation of FMD is the bioavailability of 3 to 5 times per week induced an improvement in V nitric oxide (NO), and abnormalities in 1 or more pathways 37% to 42%. A longer training period, a large variation in that ultimately regulate the availability of NO may lead to exercise intensity, and varying numbers of training sessions endothelial dysfunction. It is well established that increased per week makes comparison with the present study difficult; oxidative stress and oxidized LDL reduce the bioavailability however, the previous studies demonstrated that high exercise of NO, and in the present study, we observed that AIT intensity is associated with a large improvement of V The main goal of the present study was to evaluate the effect (P⫽0.02), which indicates a lower level of reactive oxygen of exercise when intensity was the only independent variable.
species and higher NO production. In line with this, enhanced The high-intensity exercise was chosen to be aerobic interval FMD correlated with increased total antioxidant status in exercise at 90% to 95% of peak heart rate because this blood plasma (R⫽0.67, P⬍0.01; Figure 2D). Furthermore, training method has been used by our research group in AIT reduced the plasma levels of oxidized LDL by 9% healthy individuals, yielding large improvements in V (Figure 2E; R⫽0.59, P⫽0.03).
within a relatively short time period.22 Informal comments Endurance training did not change the plasma levels of from the patients in the exercise groups indicated that patients insulin-like growth factor-1 or endothelin-1 (ET-1). After the in the AIT group found it motivating to have a varied exercise test, the median values were 2.9 (95% CI, 2.4 to 3.5) procedure to follow during each training, whereas those in the pg/mL and 61.3 (95% CI, 53.2 to 70.8) ng/mL, respectively.
MCT group found it "quite boring" to walk continuously Finally, high-sensitivity C-reactive protein was similar be- during the entire exercise period. In addition to improved tween groups and was not changed by endurance training.
˙ O2peak, improved anaerobic threshold and work economy The median high-sensitivity C-reactive protein value for all increase the patient's ability to cope with the physical groups combined was 5.6 (95% CI, 3.8 to 12.8) mg/L.
demands of daily activity.23 The present study demonstratedthat the anaerobic threshold increased more in AIT than MCT Quality of Life
when expressed in absolute workloads. Interestingly, AIT but The MacNew global score for quality of life in cardiovascular not MCT improved the patients' work economy (Table 2).
disease increased both after MCT (4.4⫾0.4 versus 5.2⫾0.2, The reason for these adaptations is not fully understood but P⬍0.01) and after AIT (4.41⫾0.32 versus 5.73⫾0.19, probably reflects improved mitochondrial function (as indi- P⬍0.001; difference between groups P⬍0.02). No change cated by an increased level of PGC-1␣) and calcium cycling occurred in the control group (4.49⫾0.24 versus 4.48⫾0.36).
in skeletal muscle of AIT patients (as suggested by increasedSERCA capacity).
The major finding of the present study was that AIT was Reversed LV Remodeling
superior to MCT in patients with postinfarction heart failure Lower plasma proBNP levels clearly demonstrate the effec- with regard to reversal of LV remodeling, aerobic capacity, tiveness of AIT in modifying postinfarction remodeling.
endothelial function, and quality of life. Of particular interest Accordingly, AIT reduced LV end-diastolic and end-systolic is the old age of the majority of patients in the present study, volumes by 18% and 25%, respectively, similar to the effect who demonstrated robust training-induced adaptation, even in of 3 months of cardiac resynchronization therapy.24 It has elderly heart failure patients. This is important information been shown that treatment with ACE inhibitors halts the because chronic heart failure is a disease of the elderly; in progression of remodeling,25 whereas combined treatment fact, it has been reported that 88% and 49% of patients with with ACE inhibitors and ␤-blockers in patients with chronic a first diagnosis of chronic heart failure were ⬎65 and ⬎80 heart failure increases ejection fraction ⬇12%26 similar to the years old, respectively.17 Despite this, most previous studies findings with AIT in the present study. These observations have excluded patients with an age ⬎70 years.
indicate that AIT utilizes a potential for further reversal ofremodeling, because it was added on top of medication.
Moreover, myocardial contractile function also markedly The large increase in V ˙ O2peak in AIT may be explained in part improved in AIT patients in terms of ejection fraction, stroke by lower baseline values and a higher exercise intensity than volume, mitral annular excursion, ejection velocity, and in previous studies (eg, Dubach et al18 and Gielen et al19), and systolic mitral annular velocity measured by tissue Doppler one could speculate whether we underestimated V before exercise but not afterward. However, this appears Ea, which is the most direct measure of LV relaxation and unlikely, because only 2 patients did not manage to satisfy the is less sensitive to load than flow indices,27 was improved in criteria defined for reaching true maximal oxygen uptake at the AIT group only. Mitral flow is a function of both left both time points. Furthermore, high blood lactate concentra- atrial pressure and LV relaxation, and the ratio of transmitral tions and high respiratory exchange ratios suggest that the flow velocity (E) versus annular velocity (Ea) has been patients exercised at maximum effort at both occasions.
proposed as an indicator of LV filling pressure.28 E/Ea Two previous studies20,21 involving patients with coronary decreased substantially in the AIT group, which indicates a artery disease have employed aerobic interval exercise with decrease in filling pressure toward normal. This is consistent elements of the same high intensity as in the present study, with the increase in isovolumic relaxation time. MCT had no both with a substantial increase of V ˙ O2peak. These studies significant effect on LV systolic or diastolic performance, showed that 12 months of exercise at 50% to 95% of V measured by tissue Doppler imaging, other than causing a

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minor improvement in the E/Ea ratio; however, the decreased other than myocardial infarction. A recent study by Rognmo E/Ea ratio in MCT was due to a small decrease in transmitral et al4 showed that a similar interval program was more than flow velocity alone and was not accompanied by supporting twice as effective in improving V ˙ O2peak compared with evidence showing an increase in E/A or isovolumic relaxation moderate-intensity exercise in patients with coronary artery time, and it might, therefore, represent a dubious result.
disease. However, the present data are provocative andshould encourage the creation of larger multicenter studies using the same training technique and addressing the safety It is well established that endurance training improves coro- nary endothelium-dependent vasodilation in patients with coronary artery disease.29 It is therefore reasonable to spec- The present study demonstrates that high-intensity training ulate that this also occurred in the present study and contrib- relative to the individual's maximal oxygen uptake is feasible uted to the antiremodeling effect of AIT in the LV.
even in elderly patients with chronic heart failure and Both the level of reactive oxygen species and the amount severely impaired cardiovascular function. It also shows that of oxidized LDL are known to directly influence NO bio- the intensity of exercise may be an important factor for availability, and a normal endothelial function is dependent reversing LV remodeling, improving aerobic capacity, and on the balance of oxidant and antioxidant mechanisms.
improving quality of life in patients with postinfarction heart During oxidative stress, superoxide anions (O ⫺ failure. These findings may have important implications for function of endothelial NO synthase and reduce the half-life exercise training in rehabilitation programs and future stud- of NO by increasing the production of peroxynitrite from NO ies. It is our view that the time has come to perform 2 , whereas in the normal state, the O2 multicenter studies comparing exercise at moderate versus superoxide dismutase. AIT improved FMD more than MCT, high relative intensities for stable cardiovascular patients, and the reason for this may be the increased bioavailability of including those with postinfarction heart failure. We suggest NO in AIT patients. In line with this notion, we found that that training programs based on these principles may yield AIT increased the antioxidant status in blood plasma, whichindicates reduced oxidative stress. These results are in agree- more favorable results than those with low to moderate ment with a recent study by Linke et al antioxidative effects of exercise training in skeletal muscle of patents with chronic heart failure. Because AIT reduced the We acknowledge assistance from professor Geir A. Espnes and amount of reactive oxygen species, it was not surprising that professor Neil Oldridge regarding the literature on quality-of-life oxidized LDL was lower in AIT. Why AIT was more effective is unknown, but it appears reasonable to speculatethat higher shear stress during the exercise bouts of AIT Sources of Funding
patients triggers larger responses at the cellular and molecular The present study was supported by grants from the Norwegian level. Despite the decreased level of reactive oxygen species Council of Cardiovascular Disease, Foundations for Cardiovascular and improved NO-mediated endothelial function, we did not and Medical Research at St. Olav's University Hospital, Trondheim,and Torstein Erbo's foundation, Trondheim. This work was also observe any change in the levels of endothelin-1 and insulin- supported by grants from the National Institutes of Health (DK like growth factor-1 in blood, which indicates that endurance 54254), the American Diabetes Association, and the United States training acts through other pathways or may act locally to Department of Agriculture (USDA 2005-38903-02315). The funding improve endothelial function.
organizations had no role in the design and conduct of the study; inthe collection, analysis, and interpretation of the data; or in the Quality of Life
preparation, review, or approval of the manuscript.
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In recent years, there has been a growing consensus that physical inactivity accelerates the severity of heart failure and thatthe level of aerobic fitness predicts survival in a cardiovascular disease population, even when other traditional risk factorsare present or in the setting of established ␤-blockade. However, there is still controversy regarding the level and formatof exercise that can yield optimal beneficial effects. In the present study, we sought to find out whether exercise intensitywas of importance for improving aerobic fitness and cardiac function in patients with postinfarction heart failure. Patientsaged 75.5⫾11.1 years either performed high-intensity aerobic interval training or moderate continuous exercise or receivedstandard advice regarding physical activity. The protocols were made isocaloric so that only exercise intensity differedbetween the 2 intervention groups. The present study demonstrates that high-intensity training relative to the individual'saerobic fitness capacity is feasible even in elderly patients with chronic heart failure who have severely impairedcardiovascular function. It also shows that the intensity of exercise is an important factor for reversing left ventricularremodeling, improving aerobic capacity, and improving quality of life in patients with postinfarction heart failure.

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