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Exercise capacity and quality of life after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction: Results from the Autologous Stem cell Transplantation in Acute Myocardial Infarction (ASTAMI) randomized controlled trial
Exercise capacity and quality of life after intracoronary injection of autologous mononuclear bone marrow cells in acute myocardial infarction: Results from the Autologous Stem cell Transplantation in Acute Myocardial Infarction (ASTAMI) randomized controlled trial Ketil Lunde, MD,a Svein Solheim, MD,b Svend Aakhus, MD, PhD,a Harald Arnesen, MD, PhD,b Torbjørn Moum, MD, PhD,c,d Michael Abdelnoor, PhD,e Torstein Egeland, MD, PhD,f Knut Endresen, MD, PhD,a Arnfinn Ilebekk, MD, PhD,g Arild Mangschau, MD, PhD,b and Kolbjørn Forfang, MD, PhDa Oslo, Norway
Background The effects on left ventricular function of intracoronary injection of bone marrow cells in acute myocardial infarction (AMI) have been studied with conflicting results. The aim of this substudy of the ASTAMI trial was to examine the effects of this novel treatment on exercise capacity and quality of life. Methods We studied 100 patients with anterior wall ST-elevation AMI. All had percutaneous coronary intervention with stent in the proximal or mid left anterior descending coronary artery 2 to 12 hours after start of symptoms. Patients were randomized to intracoronary injection of mononuclear bone marrow cells (mBMCs) in left anterior descending coronary artery 6 ± 1.3 days after AMI (n = 50) or control (n = 50). Assessment of physical capacity by maximal symptom-limited bicycle ergometer exercise tests and quality of life by the Short Form 36 health survey was performed 2 to 3 weeks and 6 months after the AMI. Results There was a significantly greater improvement in exercise time in the mBMC group than in the control group (treatment effect 0.9 minute, 95% CI 0.3-1.6, P b .01), and a similar improvement in peak oxygen consumption in the groups (2.8 ± 3.9 mL/[kg min] in the mBMC group vs 2.4 ± 3.5 mL/[kg min] in controls, P = .62). Peak heart rate and percentage of heart rate reserve increased significantly more in the treatment group than in the control group. Treatment with mBMCs did not influence quality of life. Conclusions In this randomized open-labeled study, the mBMC group significantly improved exercise time and heart rate responses to exercise compared with the control group. There was no treatment effect on peak oxygen consumption. (Am Heart J 2007;154:710.e1-710.e8.) From the aDepartment of Cardiology, Rikshospitalet-Radiumhospitalet University Hospital, Oslo, Norway, bDepartment of Cardiology, Ullevål University Hospital, Oslo, Norway, c Department of Behavioural Sciences in Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway, dDepartment of Neuropsychiatry and Psychosomatic Medicine, Division of Clinical Neuroscience, Rikshospitalet-Radiumhospitalet University hospital, Oslo, Norway, eUnit of Epidemiology and Biostatistics, Center for Clinical Research, Ullevål University Hospital, Oslo, Norway, fInstitute of Immunology, Rikshospitalet University Hospital, Oslo, Norway, and gInstitute for Experimental Medical Research, University of Oslo, Norway. Drs Lunde and Solheim are recipients of research fellowships from the Norwegian Council on Cardiovascular Diseases. ClinicalTrials.gov number: NCT00199823. Submitted March 22, 2007; accepted July 2, 2007. Reprint requests: Ketil Lunde, MD, Department of Cardiology, Rikshospitalet University Hospital, 0027 Oslo, Norway. 0002-8703/$ - see front matter © 2007, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2007.07.003
Intracoronary injection of bone marrow cells (BMCs) has been introduced as a novel approach for improvement of left ventricular function after acute myocardial infarction (AMI),1 and the change in left ventricular ejection fraction (LVEF) has typically been the primary end point in randomized clinical trials within this field. An effect on LVEF has been found in some of these studies.2,3 However, we did not confirm this in the Autologous Stem cell Transplantation in Acute Myocardial Infarction (ASTAMI) trial4; and neither did Janssens et al.5 Furthermore, there is to date no evidence for a sustained, longterm improvement of LVEF.6 Symptoms of cardiac disease generally manifest during exercise, and it is well known that resting parameters of left ventricular function correlate poorly
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with exercise capacity.7 Peak oxygen consumption . (VO2) is a stronger predictor of death than the LVEF for . patients with heart failure,8 and improvement in peak VO2 may be a more appropriate effect measure than the LVEF.9 Interestingly, exercise capacity improved after transendocardial injection of BMCs in patients with ischemic cardiomyopathy in a phase I trial10; but the potential for BMC treatment to improve exercise capacity after AMI is unknown. To our knowledge, this substudy of the randomized ASTAMI trial is the first to examine effects on exercise capacity and quality of life after intracoronary injection of BMCs in AMI.
Methods The study design has been described in detail previously.4,11 We randomized 100 patients with anterior wall AMI to intracoronary injection of mononuclear bone marrow cells (mBMCs) 4 to 8 days after the acute event (n = 50) or to a control group where neither bone marrow aspiration nor sham intracoronary injections were performed (n = 50). Three of the patients in the mBMC group did not receive intracoronary cell injections.4 All patients received medication according to current guidelines12 and were given general advice on diet, smoking, and lifestyle changes; and they were encouraged to follow cardiac rehabilitation programs at their local hospitals. Assessment of exercise capacity and quality of life was a prespecified secondary end point of the ASTAMI study.11 The study protocol was approved by the regional ethics committee, and all patients gave written informed consent. The study is registered at www.clinicaltrials.gov, NCT 00199823. The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.
Cell preparation and injection A detailed description is available in the supplementary web appendix at www.nejm.org.4 Briefly, 50 mL bone marrow was aspirated from the iliac crest in local anesthesia 4 to 7 days after percutaneous coronary intervention. Isopaque-Ficoll density gradient centrifugation was used to isolate mBMCs. Median cell viability was 95% (interquartile range 94-97), and median number of injected viable mBMCs was 68 × 106 (interquartile range 54 × 106 to 130 × 106). The median number of CD34+ cells was 0.7 × 106 cells (interquartile range 0.4 × 106 to 1.6 × 106 cells). All cell preparations were performed in an ex vivo cell processing laboratorium under good manufacturing practice conditions. A percutaneous coronary intervention stop-flow technique1 was used for intracoronary mBMC injections distally to the culprit lesion in the left anterior descending coronary artery. There were 3 balloon inflations of 1.5 minutes for no-flow during injections, separated by 5 minutes of balloon deflation for reflow between injections.
Exercise capacity Maximal symptom-limited tests were performed 2 to 3 weeks and 6 months after the AMI with an electrically braked bicycle
Table I. Patient characteristics mBMC group Control group (n= 50) (n= 50) Baseline characteristics Age (y) Female Body mass index (kg/m2) Hypertension Diabetes mellitus Current smokers LVEF by SPECT (%) LVEDV by SPECT (mL) Infarct size by SPECT (%) 1/2/3-Vessel disease Values at 2-3 wk Current smokers Systolic BP at rest (mm Hg) Diastolic BP at rest (mm Hg) Heart rate at rest (bounds/min) Medication* β-Blockers Metoprolol succinate extended release Metoprolol (mg/d) ACE inhibitors/ angiotensin receptor blockers Calcium-channel blockers Nitrates Values at 6 m Current smokers Systolic BP at rest (mm Hg) Diastolic BP at rest (mm Hg) Heart rate at rest (bounds/min) Medication β-Blockers Metoprolol succinate extended release Metoprolol (mg/d) ACE inhibitors/ angiotensin receptor blockers Calcium-channel blockers Nitrates
P
58.1 ± 8.5 8 (16%) 26.3 ± 3.8 17 (34%) 5 (10%) 20 (40%) 41.3 ± 10.4 162.3 ± 59.1 43.8 ± 17.4 42/6/2
56.7 ± 9.6 8 (16%) 27.1 ± 3.5 17 (34%) 4 (8%) 24 (48%) 42.6 ± 11.7 148.0 ± 46.3 38.3 ± 21.1 36/12/2
.42 1.00 .30 1.00 .73 .72 .57 .19 .16 .29
6 (12%) 113 ± 18 73 ± 11 68 ± 13
6 (12%) 116 ± 16 74 ± 9 64 ± 13
1.00 .48 .33 .11
50 (98%) 49 (98%)
50 (100%) 49 (98%)
1.00 1.00
103 ± 56 50 (100%)
91 ± 54 50 (100%)
.28 1.00
0
0
1.00
0
0
1.00
7 (14%) 125 ± 20 74 ± 10 57 ± 10
6 (12%) 123 ± 18 73 ± 10 59 ± 9
.77 .65 .60 .53
50 (100%) 49 (98%)
50 (100%) 47 (94%)
1.00 .62
102 ± 52 50 (100%)
98 ± 54 50 (100%)
.72 1.00
1
0
1.00
1
0
1.00
Values are mean ± SD or patient number (proportion). SPECT, Single photon emission computed tomography; LVEDV, left ventricular end-diastolic volume; BP, blood pressure. *All patients used aspirin, clopidogrel, and a statin during the study except for one control group patient at 2 to 3 weeks and 2 control group patients at 6 months not taking a statin.
ergometer (Jaeger ER900, VIASYS Healthcare GmbH, Hochberg, Germany) according to standard criteria.13 At the day of exercise testing, a light meal, but no caffeinated beverages or smoking, was allowed in advance. At 2 to 3 weeks, there were no medication restrictions. At the day of 6-month exercise testing, β-blockers, calcium-channel blockers, and nitrates were postponed to after the test; and other medications were taken as usual. Stepwise exercise protocols were chosen to obtain a
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Table II. Bicycle ergometer exercise testing 2-3 wk
. Peak VO2 (mL/[kg min]) AT (mL/[kg min]) Max load (W) Exercise time (min) Time to AT (min) Peak heart rate (bounds/min) Peak systolic BP (mm Hg) Peak DP (mm Hg/ [bounds min])103 %HRR Heart rate recovery VE/VCO2 slope OUES
6m
Change
mBMC group
Control group
mBMC group
Control group
mBMC group
Control group
19.8 ± 6.4 n = 47 16.4 ± 5.2 n = 42 133 ± 41 n = 47 8.6 ± 2.8 n = 47 6.2 ± 2.2 n = 42 124.9 ± 23.5 n = 47 161 ± 32 n = 46 20.5 ± 6.3 n = 47 60.9 ± 23.8 n = 47 20.7 ± 8.7 n = 46 31.9 ± 4.9 n = 46 2.22 ± 0.68 n = 46
18.8 ± 6.5 n = 43 14.8 ± 4.4 n = 39 136 ± 55 n = 43 8.8 ± 2.6 n = 43 6.2 ± 1.9 n = 39 122.5 ± 20.4 n = 43 167 ± 32 n = 40 20.7 ± 6.1 n = 40 58.0 ± 18.9 n = 43 23.0 ± 9.3 n = 42 30.5 ± 4.0 n = 43 2.25 ± 0.71 n = 43
22.4 ± 7.2 n = 49 17.7 ± 5.5 n = 48 154 ± 51 n = 49 10.6 ± 3.2 n = 49 7.2 ± 2.8 n = 49 143.4 ± 20.7 n = 49 185 ± 35 n = 46 26.8 ± 6.0 n = 46 82.6 ± 17.6 n = 49 26.4 ± 13.7 n = 49 31.8 ± 4.0 n = 49 2.43 ± 0.68 n = 49
20.9 ± 6.3 n = 49 16.6 ± 5.2 n = 46 149 ± 53 n = 50 9.9 ± 2.9 n = 50 6.8 ± 2.5 n = 46 137.9 ± 18.8 n = 50 179 ± 29 n = 46 25.1 ± 5.7 n = 46 76.4 ± 18.9 n = 50 28.0 ± 14.4 n = 49 31.2 ± 4.3 n = 48 2.28 ± 0.68 n = 48
2.8 ± 3.9 n = 46 1.7 ± 3.4 n = 42 23 ± 24 n = 46 2.1 ± 1.9 n = 46 1.3 ± 1.8 n = 42 18.5 ± 16.3 n = 46 24 ± 37 n = 43 6.4 ± 6.6 n = 43 21.5 ± 16.9 n = 46 4.7 ± 11.1 n = 46 −0.05 ± 3.5 n = 46 0.18 ± 0.48 n = 46
2.4 ± 3.5 n = 42 2.4 ± 3.5 n = 36 13 ± 16 n = 43 1.2 ± 1.3 n = 43 1.0 ± 1.9 n = 36 13.3 ± 15.8 n = 43 16 ± 22 n = 37 4.4 ± 4.3 n = 37 15.6 ± 15.8 n = 43 5.3 ± 12.5 n = 41 0.04 ± 3.1 n = 41 0.13 ± 0.41 n = 41
Treatment effect
P
(95% CI) 0.4 (−1.2 to 2.0)
.62
−0.4 (−2.0 to 1.2)
.61
10 (2 to 19)
b.05
0.9 (0.3 to 1.6)
b.01
0.3 (−0.6 to 1.1)
.52
6.0 (0.2 to 11.7)
b.05
7 (−6 to 19)
.28
1.9 (−0.3 to 4.1)
.09
7.2 (1.6 to 12.7)
b.05
−1.1 (−6.1 to 3.9)
.67
0.3 (−0.9 to 1.6)
.60
0.06 (−0.12 to 0.25)
.50
The changes from 2 to 3 weeks to 6 months were calculated from patients for whom data from both time points were available. Treatment effects and P values were obtained from these data with ANCOVA.
test length of approximately 10 minutes, starting at 25 or 50 W and with a 10-, 25-, or 50-W increase every second minute. Pedaling rate was kept at approximately 60 rotations per minute, and each patient used the same protocol for repeated testing. The flow sensor and the O2 and CO2 sensors were calibrated before each test. Oxygen consumption, carbon dioxide . production (VcO2), and ventilation (VE) were measured on a breath-by-breath basis (MVmax 229, VIASYS Healthcare GmbH, Hoechberg, Germany). All reported values are averaged over 20-second sampling intervals, except for a 30-second sampling interval for the anaerobic threshold (AT). Heart rate was continuously recorded from a 12-lead electrocardiogram, brachial artery blood pressure was measured at the end of each step using an automatic inflatable cuff and a microphone transducer, and exercise time was recorded. . . Maximal VO2 (peak VO2) and the respiratory exchange ratio . . (RER) calculated as VCO2/VO2 were taken at the end of tests. The . AT is given as VO2 at the point where VE begins to increase exponentially for a given increase in oxygen uptake. The AT was determined with the V-slope method when possible; otherwise, . the VE/VO2 method or the point at which a systematic rise in end-tidal oxygen pressure occurs without a decrease in the endtidal carbon dioxide pressure (PETO2) method was used.14 The VE/V̇cO2 slope was determined with the MVmax 229 software plot view function using linear regression of all data obtained during exercise.15 For the oxygen uptake
efficiency slope (OUES),16 data from the second 20-second interval after the start, at the AT, and at peak values were used. The slope calculation option of the Microsoft Excel software (Microsoft, Redmond, WA) was used for calculation of the best-fit linear regression line relating log10VE . and VO2. . Peak heart rate was averaged from the peak VO2 20-second sampling interval. Percentage of heart rate reserve (%HRR) was calculated as ([peak heart rate − resting heart rate]/[220 − age − resting heart rate]) × 100.17 Heart rate recovery was calculated as the difference between peak heart rate and heart rate at 60 seconds after exercise termination. Peak double product (DP) was calculated as peak heart rate × peak systolic blood pressure. Dyspnea was graded according to the New York Heart Association (NYHA) classification system based on standardized interviews at 2 to 3 weeks and at 6 months of follow-up.
Quality of life To assess changes in health-related quality of life, patients answered the Norwegian version 1.2 of the Short Form (SF) 36 questionnaire at 2 to 3 weeks and at 6 months after the infarction. Responses were related at 2 to 3 weeks to the period from primary discharge and at 6 months to the last 4 weeks. Scores18 were weighted and aggregated using normative data from the general Norwegian population19 to
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Figure 1
. Exercise time, peak heart rate, and peak VO2 at 2 to 3 weeks and 6 months after myocardial infarction. In the left panels, solid circles represent the mean values with SD error bars; and thin lines represent the change over time for individual patients. In the right panels, bars represent mean values with SEM error bars.
obtain a physical component summary (PCS) and mental component summary (MCS) score.20 The lowest possible score for both composites is 0; and the highest score is 100, with higher values indicating better health. In the general
population, mean PCS and MCS scores are 50 with SD of 10. A difference of ≥3 points between groups in the change scores (6 months − 2 to 3 weeks) of PCS or MCS was considered to be of clinical significance.20
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Table III. NYHA class mBMC 2-3 wk I II III IV 6m I II III IV Change Improvement ≥1 class Unchanged Worsening ≥1 class
Control
P .33
28 (56%) 18 (45%) 4 (8%) 0
27 (54%) 22 (44%) 1 (2%) 0
37 (74%) 12 (24%) 1 (2%) 0
35 (70%) 14 (28%) 1 (2%) 0
18 (36%) 25 (50%) 7 (14%)
12 (24%) 34 (68%) 4 (8%)
.90
.18
Statistical methods Continuous variables that approximated a normal distribution are presented as mean ± SD, and 2-sample t tests were performed for comparing groups. Treatment effects were calculated with analysis of covariance (ANCOVA), with the baseline value used as a covariate. Continuous variables with a skewed distribution are presented as median (interquartile range). Categorical parameters are presented as frequencies (proportion). Groups were compared with the χ2 test or Fisher exact test as appropriate. The NYHA class change scores (6 months − 2 to 3 weeks) were calculated for testing treatment effects with the χ2 test. All analyses were performed according to the intention-to-treat principle. Twosided tests have been used throughout, and P values b .05 were considered to indicate statistical significance. All statistical analyses were performed with SPSS software version 14.0 (SPSS, Chicago, IL).
Results There were no differences between groups in patient characteristics (Table I). All patients used β-blockers at both time points. During the follow-up period, 24 patients (48%) in the mBMC group and 22 (44%) in the control group followed organized cardiac rehabilitation programs (P = .62 for difference between groups); and 43 (86%) in the mBMC group and 41 (82%) in the control group reported regular individual physical exercise of ≥20 minutes ≥1× per week (P = .56). Of the patients who were smokers at baseline, 13 of 20 in the mBMC group had stopped smoking at 6-month follow-up, compared with 18 of 24 in the control group (P = .47). At 2 to 3 weeks, 47 patients (94%) in the mBMC group and 43 (86%) in the control group underwent exercise testing. At 6 months, the numbers were 49 (98%) and 50 (100%), respectively. The main reason for not performing exercise test at baseline was echocardiographic evidence of left ventricular thrombus (n = 2 in the mBMC group
and n = 7 in the control group). One patient in the mBMC group refused exercise testing.
Functional capacity There were no adverse events in relation to exercise testing, and there were no differences between groups for exercise parameters at 2 to 3 weeks. At 2 to 3 weeks, the RER was 1.13 ± 0.08 in the mBMC group and 1.12 ± 0.07 in the control group (P = .55); at 6 months, it was 1.13 ± 0.07 and 1.12 ± 0.07 (P = .82), respectively. The AT was reached by 42 patients (91%) in the mBMC group and by 39 (91%) in the control group at 2 to 3 weeks (P = 1.00), and by 49 (98%) and 46 (96%), respectively, at 6 months (P = .61). The reason for termination of exercise at 2 to 3 weeks was lower limb pain in 66 patients (73%), dyspnea in 22 (24%), chest pain in 1 (1%), premature ventricular contractions in 1 (1%), and dizziness in 1 (1%). At 6 months, exercise was terminated because of lower limb pain in 85 patients (86%), dyspnea in 12 (12%), and chest paint in 2 (2%). There were no differences between groups for reasons of test termination. There was a significant correlation between the change . in exercise time and the change in peak VO2 in both groups (r = 0.52, P b .001 in the mBMC group; r = 0.37, P b .05 in the control group). At 6 months, there was a . modest increase in peak VO2 and AT in both groups, but without a significant difference between groups (Table II). Exercise time increased significantly more in the mBMC group than in the control group. Time to AT increased similarly in both groups. Peak heart rate and % HRR increased significantly more in the mBMC group than in the control group, and heart rate recovery . increased similarly in both groups. The VCO2 slope was similar in both groups and unchanged from 2 to 3 weeks to 6 months. This was also the case when only data before the AT were used (data not shown). There was a similar modest increase in the OUES in both groups. Individual . responses for exercise time, peak heart rate, and peak VO2 are illustrated in Figure 1. Symptoms There were no differences between groups for the change in symptoms of dyspnea as measured by NYHAclass (Table III). Quality of life The MCS score was mainly unchanged in both groups, whereas there was a similar increase in the PCS score (Table IV). There were no significant differences between groups for the changes in MCS score or PCS score.
Discussions The main finding in this randomized open-labeled study is that patients treated with intracoronary
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Table IV. Quality of life (SF-36) 2-3 wk
PCS MCS
6m
Change
mBMC group
Control group
mBMC group
Control group
mBMC group
Control group
40.9 ± 11.1 n = 37 48.4 ± 10.9 n = 37
42.0 ± 7.4 n = 39 48.2 ± 11.6 n = 39
47.4 ± 8.9 n = 46 51.2 ± 10.7 n = 46
47.7 ± 9.1 n = 45 50.6 ± 8.8 n = 45
5.8 ± 11.2 n = 36 1.2 ± 11.4 n = 36
6.0 ± 9.3 n = 39 2.1 ± 11.9 n = 39
Treatment effect
(95% CI)
P
−0.9 (−4.7 to 2.9)
.66
−0.4 (−4.6 to 3.8)
.86
The change from 2 to 3 weeks to 6 months was calculated from patients for whom data from both time points were available. Treatment effects and P values were obtained from these data with ANCOVA.
injection of autologous mBMCs a few days after anterior wall AMI significantly improved exercise time and heart . rate responses to exercise, but not peak VO2, as compared with the control group. All patients received the best medical treatment. Approximately every second patient followed organized cardiac rehabilitation programs, and this was similar in both groups. We did not find any significant treatment effects for symptoms of heart failure by NYHA class or quality of life assessed by the SF-36 questionnaire. The obvious question to raise is whether the observed improvement in exercise time represents a true treatment effect of intracoronary mBMC injection or a placebo effect. Although excellent correlation between exercise time and oxygen uptake has been demonstrated for bicycle exercise tests, 21 direct measurement of ventilatory gases provides the best validated and most accurate . measure of exercise capacity13; and peak VO2 is a powerful predictor of mortality.8 However, although both β-blockers and angiotensin-converting enzyme (ACE) inhibitors improved prognosis after AMI,12 neither . β-blockers22 nor ACE inhibitors23 improved peak VO2 in patients with heart failure predominately caused by ischemic heart disease. Furthermore, measurement of . peak VO2 is also influenced by patient motivation.24 The similar RER values in the groups at both baseline and 6 months indicate similar effort during exercise. However, the RER is an indirect measurement of the tissue respiratory quotient; and the RER is also influenced by other factors such as hyperventilation.25 Therefore, other indices for accurate measurement of exercise capacity that may be unaffected by patient motivation have been suggested. . Anaerobic threshold correlates well with peak VO226 and can be used as a less effort-dependent measure of exercise capacity.27 We found no indication of a positive effect of mBMC treatment when the AT or the time to AT was measured. However, the use of AT is complicated by methodological issues.14 Because the OUES is linear during exercise, it is a valuable tool for the assessment of exercise capacity . when submaximal levels are reached.16 The VE/VCO2
slope has been most extensively studied as a prognostic marker, but this parameter also correlates with the symptoms and severity of heart failure.28 The similar increase in OUES and the unchanged VE/V̇CO2 slope in the randomized groups from 2 to 3 weeks to 6 months do not support a true treatment effect in the current study. Both peak heart rate and the %HRR increased significantly more in the mBMC group than in the control group, and we also found a trend in favor of the mBMC group for the improvement in the peak DP. The improvement in heart rate response to exercise may indicate a beneficial effect of mBMC treatment. The %HRR is a strong predictor of mortality,17 and heart rate responses to exercise are related to the severity of heart failure.29 Increased peak heart rate may however have been related to patient motivation. Heart rate recovery, on the other hand, reflects vagal activity, is correlated with exercise capacity, and is unrelated to the intensity of exercise.30 Therefore, it may be less influenced by patient motivation. The similar response in heart rate recovery in the randomized groups indicates that the difference in heart rate responses to exercise is mediated by a placebo effect. Compared with similar trials,2,3,5 we injected a smaller number of cells. Because there is no correlation between the number of cells injected and the improvement in cardiac function,2,4,31 too low cell numbers can probably not explain why we did not observe a definite effect on exercise capacity after mBMC treatment. One study suggests that subtle differences in cell preparation may be of importance.32 However, the relevance of differences in in vitro studies and in the mouse hind-limb ischemia model to explain differences between studies of BMC treatment after myocardial infarction in humans remains elusive. More likely, our results confirm the limitations of intracoronary injection of unfractioned BMCs in acute AMI. The BOOST study ended up as a negative study with regard to the primary end point, which was the change in LVEF.6 Janssens et al found that mBMCs reduced infarct size and transiently improved regional
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left ventricular function compared with placebo, but also failed to show an effect on LVEF, which was the primary end point.5 In the REPAIR-AMI study,3 a small treatment effect on the LVEF was observed. Unfortunately, single-plane angiocardiography was used for the assessment of left ventricular function. Because this method is inaccurate in these patients with wall motion abnormalities,33 it is difficult to draw firm conclusions about efficacy from the results of the REPAIR-AMI study.
Study limitations In this open-labeled study, patients in the treatment group may have been more motivated for lifestyle changes. The similar rates for smoking cessation in the groups argue against this. Our results are confined to the methods used and the relatively short observation period of 6 months. A positive treatment effect may potentially be observed after a longer follow-up period. For safety reasons, baseline recordings were obtained 2 to 3 weeks after the acute event; and the absolute values for changes in exercise capacity after AMI may have been underestimated in both groups. Although the ASTAMI study is the second largest study to date on BMC treatment in AMI, it may have been underpowered to . detect small improvements in peak VO2 and quality of life. Conclusions The observed improvement in exercise time after intracoronary injection of autologous mBMCs a few days after AMI may indicate a positive treatment effect, and a possible mechanism is the improvement in the chronotropic response to exercise. However, the mBMC group did not benefit compared with the control group when . the more objective measures such as the peak VO2, AT and . time to AT, heart rate recovery, VE/VCO2 slope, or OUES were used. We are indebted to Lars Gullestad (Department of Cardiology, Rikshospitalet University Hospital), Jostein Hallén (Norwegian School of Sports Sciences), and Per Morten Fredriksen (Department of Physiotherapy, Rikshospitalet University Hospital) for comments on the interpretation of exercise testing and to the staff at the Department of Cardiology at Rikshospitalet University Hospital for assistance during the exercise tests.
References 1. Strauer BE, Brehm M, Zeus T, et al. Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation 2002;106:1913-8. 2. Wollert KC, Meyer GP, Lotz J, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004;364:141-8.
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3. Schächinger V, Erbs S, Elsässer A, et al. Intracoronary bone marrow– derived progenitor cells in acute myocardial infarction. N Engl J Med 2006;355:1210-21. 4. Lunde K, Solheim S, Aakhus S, et al. Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. N Engl J Med 2006;355:1199-209. 5. Janssens S, Dubois C, Bogaert J, et al. Autologous bone marrow– derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 2006;367:113-21. 6. Meyer GP, Wollert KC, Lotz J, et al. Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months' follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to enhance ST-elevation infarct regeneration) trial. Circulation 2006;113:1287-94. 7. Franciosa JA, Park M, Barry Levine T. Lack of correlation between exercise capacity and indexes of resting left ventricular performance in heart failure. Am J Cardiol 1981;47:33-9. 8. Myers J, Gullestad L, Vagelos R, et al. Clinical, hemodynamic, and cardiopulmonary exercise test determinants of survival in patients referred for evaluation of heart failure. Ann Intern Med 1998;129:286-93. 9. Niebauer J, Clark AL, Anker SD, et al. Three year mortality in heart failure patients with very low left ventricular ejection fractions. Int J Cardiol 1999;70:245-7. 10. Perin EC, Dohmann HFR, Borojevic R, et al. Improved exercise capacity and ischemia 6 and 12 months after transendocardial injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy. Circulation 2004;110:II-213. 11. Lunde K, Solheim S, Aakhus S, et al. Autologous stem cell transplantation in acute myocardial infarction: the ASTAMI randomized controlled trial. Intracoronary transplantation of autologous mononuclear bone marrow cells, study design and safety aspects. Scand Cardiovasc J 2005;39:150-8. 12. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction. Circulation 2004;110:e82-e292. 13. Arena R, Myers J, Williams MA, et al. Assessment of functional capacity in clinical and research settings. A scientific statement from the American Heart Association Committee on Exercise, Rehabilitation, and Prevention of the Council on Clinical Cardiology and the Council on Cardiovascular Nursing. Circulation 2007;116: 329-43. 14. Shimizu M, Myers J, Buchanan N, et al. The ventilatory threshold: method, protocol, and evaluator agreement. Am Heart J 1991;122: 509-16. 15. Bard RL, Gillespie BW, Clarke NS, et al. Determining the best ventilatory efficiency measure to predict mortality in patients with heart failure. J Heart Lung Transpl 2006;25:589-95. 16. Baba R, Nagashima M, Goto M, et al. Oxygen uptake efficiency slope: a new index of cardiorespiratory functional reserve derived from the relation between oxygen uptake and minute ventilation during incremental exercise. J Am Coll Cardiol 1996;28:1567-72. 17. Azarbal B, Hayes SW, Lewin HC, et al. The incremental prognostic value of percentage of heart rate reserve achieved over myocardial perfusion single-photon emission computed tomography in the prediction of cardiac death and all-cause mortality: superiority over 85% of maximal age-predicted heart rate. J Am Coll Cardiol 2004;44:423-30. 18. Ware JE. SF-36 health survey. Manual & interpretation guide. Boston (Mass): The Health Institute, New England Medical Center; 1993.
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19. Loge JH, Kaasa S. Short form 36 (SF-36) health survey: normative data from the general Norwegian population. Scand J Soc Med 1998;26:250-8. 20. Ware JE. SF-36 physical and mental health summary scales: a user's manual. Boston (Mass): The Health Institute, New England Medical Center; 1994. 21. Page E, Cohen-Solal A, Jondeau G, et al. Comparison of treadmill and bicycle exercise in patients with chronic heart failure. Chest 1994;106:1002-6. 22. Gullestad L, Manhenke C, Aarsland T, et al. Effect of metoprolol CR/ XL on exercise tolerance in chronic heart failure—a substudy to the MERIT-HF trial. Eur J Heart Fail 2001;3:463-8. 23. Cohn JN, Johnson G, Ziesche S, et al. A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure. N Engl J Med 1991;325:303-10. 24. Wright DJ, Tan LB. Classic techniques in medicine: the role of exercise testing in the evaluation and management of heart failure. Postgrad Med J 1999;75:453-8. 25. Clark AL. Exercise and heart failure: assessment and treatment. Heart 2006;92:699-703. 26. Lipkin DP, Bayliss J, Poole-Wilson PA. The ability of a submaximal exercise test to predict maximal exercise capacity in patients with heart failure. Eur Heart J 1985;6:829-33.
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27. Fletcher GF, Balady GJ, Amsterdam EA, et al. Exercise standards for testing and training: a statement for healthcare professionals from the American Heart Association. Circulation 2001;104:1694-740. 28. Clark AL. Origin of symptoms in chronic heart failure. Heart 2006;92:12-6. 29. Witte KKA, Cleland JGF, Clark AL. Chronic heart failure, chronotropic incompetence, and the effects of β-blockade. Heart 2006;92:481-6. 30. Imai K, Sato H, Hori M, et al. Vagally mediated heart rate recovery after exercise is accelerated in athletes but blunted in patients with chronic heart failure. J Am Coll Cardiol 1994;24:1529-35. 31. Britten MB, Abolmaali ND, Assmus B, et al. Infarct remodeling after intracoronary progenitor cell treatment in patients with acute myocardial infarction (TOPCARE-AMI): mechanistic insights from serial contrast-enhanced magnetic resonance imaging. Circulation 2003;108:2212-8. 32. Seeger FH, Tonn T, Krzossok N, et al. Cell isolation procedures matter: a comparison of different isolation protocols of bone marrow mononuclear cells used for cell therapy in patients with acute myocardial infarction. Eur Heart J 2007;28:766-72. 33. Grebe O, Kestler HA, Merkle N, et al. Assessment of left ventricular function with steady-state-free-precession magnetic resonance imaging. Reference values and a comparison to left ventriculography. Z Kardiol 2004;93:686-95.
Background The effects on left ventricular function of intracoronary injection of bone marrow cells in acute myocardial infarction (AMI) have been studied with conflicting results. The aim of this substudy of the ASTAMI trial was to examine the effects of this novel treatment on exercise capacity and quality of life. Methods We studied 100 patients with anterior wall ST-elevation AMI. All had percutaneous coronary intervention with stent in the proximal or mid left anterior descending coronary artery 2 to 12 hours after start of symptoms. Patients were randomized to intracoronary injection of mononuclear bone marrow cells (mBMCs) in left anterior descending coronary artery 6 ± 1.3 days after AMI (n = 50) or control (n = 50). Assessment of physical capacity by maximal symptom-limited bicycle ergometer exercise tests and quality of life by the Short Form 36 health survey was performed 2 to 3 weeks and 6 months after the AMI. Results There was a significantly greater improvement in exercise time in the mBMC group than in the control group (treatment effect 0.9 minute, 95% CI 0.3-1.6, P b .01), and a similar improvement in peak oxygen consumption in the groups (2.8 ± 3.9 mL/[kg min] in the mBMC group vs 2.4 ± 3.5 mL/[kg min] in controls, P = .62). Peak heart rate and percentage of heart rate reserve increased significantly more in the treatment group than in the control group. Treatment with mBMCs did not influence quality of life. Conclusions In this randomized open-labeled study, the mBMC group significantly improved exercise time and heart rate responses to exercise compared with the control group. There was no treatment effect on peak oxygen consumption. (Am Heart J 2007;154:710.e1-710.e8.) From the aDepartment of Cardiology, Rikshospitalet-Radiumhospitalet University Hospital, Oslo, Norway, bDepartment of Cardiology, Ullevål University Hospital, Oslo, Norway, c Department of Behavioural Sciences in Medicine, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway, dDepartment of Neuropsychiatry and Psychosomatic Medicine, Division of Clinical Neuroscience, Rikshospitalet-Radiumhospitalet University hospital, Oslo, Norway, eUnit of Epidemiology and Biostatistics, Center for Clinical Research, Ullevål University Hospital, Oslo, Norway, fInstitute of Immunology, Rikshospitalet University Hospital, Oslo, Norway, and gInstitute for Experimental Medical Research, University of Oslo, Norway. Drs Lunde and Solheim are recipients of research fellowships from the Norwegian Council on Cardiovascular Diseases. ClinicalTrials.gov number: NCT00199823. Submitted March 22, 2007; accepted July 2, 2007. Reprint requests: Ketil Lunde, MD, Department of Cardiology, Rikshospitalet University Hospital, 0027 Oslo, Norway. 0002-8703/$ - see front matter © 2007, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2007.07.003
Intracoronary injection of bone marrow cells (BMCs) has been introduced as a novel approach for improvement of left ventricular function after acute myocardial infarction (AMI),1 and the change in left ventricular ejection fraction (LVEF) has typically been the primary end point in randomized clinical trials within this field. An effect on LVEF has been found in some of these studies.2,3 However, we did not confirm this in the Autologous Stem cell Transplantation in Acute Myocardial Infarction (ASTAMI) trial4; and neither did Janssens et al.5 Furthermore, there is to date no evidence for a sustained, longterm improvement of LVEF.6 Symptoms of cardiac disease generally manifest during exercise, and it is well known that resting parameters of left ventricular function correlate poorly
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with exercise capacity.7 Peak oxygen consumption . (VO2) is a stronger predictor of death than the LVEF for . patients with heart failure,8 and improvement in peak VO2 may be a more appropriate effect measure than the LVEF.9 Interestingly, exercise capacity improved after transendocardial injection of BMCs in patients with ischemic cardiomyopathy in a phase I trial10; but the potential for BMC treatment to improve exercise capacity after AMI is unknown. To our knowledge, this substudy of the randomized ASTAMI trial is the first to examine effects on exercise capacity and quality of life after intracoronary injection of BMCs in AMI.
Methods The study design has been described in detail previously.4,11 We randomized 100 patients with anterior wall AMI to intracoronary injection of mononuclear bone marrow cells (mBMCs) 4 to 8 days after the acute event (n = 50) or to a control group where neither bone marrow aspiration nor sham intracoronary injections were performed (n = 50). Three of the patients in the mBMC group did not receive intracoronary cell injections.4 All patients received medication according to current guidelines12 and were given general advice on diet, smoking, and lifestyle changes; and they were encouraged to follow cardiac rehabilitation programs at their local hospitals. Assessment of exercise capacity and quality of life was a prespecified secondary end point of the ASTAMI study.11 The study protocol was approved by the regional ethics committee, and all patients gave written informed consent. The study is registered at www.clinicaltrials.gov, NCT 00199823. The authors had full access to the data and take responsibility for its integrity. All authors have read and agree to the manuscript as written.
Cell preparation and injection A detailed description is available in the supplementary web appendix at www.nejm.org.4 Briefly, 50 mL bone marrow was aspirated from the iliac crest in local anesthesia 4 to 7 days after percutaneous coronary intervention. Isopaque-Ficoll density gradient centrifugation was used to isolate mBMCs. Median cell viability was 95% (interquartile range 94-97), and median number of injected viable mBMCs was 68 × 106 (interquartile range 54 × 106 to 130 × 106). The median number of CD34+ cells was 0.7 × 106 cells (interquartile range 0.4 × 106 to 1.6 × 106 cells). All cell preparations were performed in an ex vivo cell processing laboratorium under good manufacturing practice conditions. A percutaneous coronary intervention stop-flow technique1 was used for intracoronary mBMC injections distally to the culprit lesion in the left anterior descending coronary artery. There were 3 balloon inflations of 1.5 minutes for no-flow during injections, separated by 5 minutes of balloon deflation for reflow between injections.
Exercise capacity Maximal symptom-limited tests were performed 2 to 3 weeks and 6 months after the AMI with an electrically braked bicycle
Table I. Patient characteristics mBMC group Control group (n= 50) (n= 50) Baseline characteristics Age (y) Female Body mass index (kg/m2) Hypertension Diabetes mellitus Current smokers LVEF by SPECT (%) LVEDV by SPECT (mL) Infarct size by SPECT (%) 1/2/3-Vessel disease Values at 2-3 wk Current smokers Systolic BP at rest (mm Hg) Diastolic BP at rest (mm Hg) Heart rate at rest (bounds/min) Medication* β-Blockers Metoprolol succinate extended release Metoprolol (mg/d) ACE inhibitors/ angiotensin receptor blockers Calcium-channel blockers Nitrates Values at 6 m Current smokers Systolic BP at rest (mm Hg) Diastolic BP at rest (mm Hg) Heart rate at rest (bounds/min) Medication β-Blockers Metoprolol succinate extended release Metoprolol (mg/d) ACE inhibitors/ angiotensin receptor blockers Calcium-channel blockers Nitrates
P
58.1 ± 8.5 8 (16%) 26.3 ± 3.8 17 (34%) 5 (10%) 20 (40%) 41.3 ± 10.4 162.3 ± 59.1 43.8 ± 17.4 42/6/2
56.7 ± 9.6 8 (16%) 27.1 ± 3.5 17 (34%) 4 (8%) 24 (48%) 42.6 ± 11.7 148.0 ± 46.3 38.3 ± 21.1 36/12/2
.42 1.00 .30 1.00 .73 .72 .57 .19 .16 .29
6 (12%) 113 ± 18 73 ± 11 68 ± 13
6 (12%) 116 ± 16 74 ± 9 64 ± 13
1.00 .48 .33 .11
50 (98%) 49 (98%)
50 (100%) 49 (98%)
1.00 1.00
103 ± 56 50 (100%)
91 ± 54 50 (100%)
.28 1.00
0
0
1.00
0
0
1.00
7 (14%) 125 ± 20 74 ± 10 57 ± 10
6 (12%) 123 ± 18 73 ± 10 59 ± 9
.77 .65 .60 .53
50 (100%) 49 (98%)
50 (100%) 47 (94%)
1.00 .62
102 ± 52 50 (100%)
98 ± 54 50 (100%)
.72 1.00
1
0
1.00
1
0
1.00
Values are mean ± SD or patient number (proportion). SPECT, Single photon emission computed tomography; LVEDV, left ventricular end-diastolic volume; BP, blood pressure. *All patients used aspirin, clopidogrel, and a statin during the study except for one control group patient at 2 to 3 weeks and 2 control group patients at 6 months not taking a statin.
ergometer (Jaeger ER900, VIASYS Healthcare GmbH, Hochberg, Germany) according to standard criteria.13 At the day of exercise testing, a light meal, but no caffeinated beverages or smoking, was allowed in advance. At 2 to 3 weeks, there were no medication restrictions. At the day of 6-month exercise testing, β-blockers, calcium-channel blockers, and nitrates were postponed to after the test; and other medications were taken as usual. Stepwise exercise protocols were chosen to obtain a
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Table II. Bicycle ergometer exercise testing 2-3 wk
. Peak VO2 (mL/[kg min]) AT (mL/[kg min]) Max load (W) Exercise time (min) Time to AT (min) Peak heart rate (bounds/min) Peak systolic BP (mm Hg) Peak DP (mm Hg/ [bounds min])103 %HRR Heart rate recovery VE/VCO2 slope OUES
6m
Change
mBMC group
Control group
mBMC group
Control group
mBMC group
Control group
19.8 ± 6.4 n = 47 16.4 ± 5.2 n = 42 133 ± 41 n = 47 8.6 ± 2.8 n = 47 6.2 ± 2.2 n = 42 124.9 ± 23.5 n = 47 161 ± 32 n = 46 20.5 ± 6.3 n = 47 60.9 ± 23.8 n = 47 20.7 ± 8.7 n = 46 31.9 ± 4.9 n = 46 2.22 ± 0.68 n = 46
18.8 ± 6.5 n = 43 14.8 ± 4.4 n = 39 136 ± 55 n = 43 8.8 ± 2.6 n = 43 6.2 ± 1.9 n = 39 122.5 ± 20.4 n = 43 167 ± 32 n = 40 20.7 ± 6.1 n = 40 58.0 ± 18.9 n = 43 23.0 ± 9.3 n = 42 30.5 ± 4.0 n = 43 2.25 ± 0.71 n = 43
22.4 ± 7.2 n = 49 17.7 ± 5.5 n = 48 154 ± 51 n = 49 10.6 ± 3.2 n = 49 7.2 ± 2.8 n = 49 143.4 ± 20.7 n = 49 185 ± 35 n = 46 26.8 ± 6.0 n = 46 82.6 ± 17.6 n = 49 26.4 ± 13.7 n = 49 31.8 ± 4.0 n = 49 2.43 ± 0.68 n = 49
20.9 ± 6.3 n = 49 16.6 ± 5.2 n = 46 149 ± 53 n = 50 9.9 ± 2.9 n = 50 6.8 ± 2.5 n = 46 137.9 ± 18.8 n = 50 179 ± 29 n = 46 25.1 ± 5.7 n = 46 76.4 ± 18.9 n = 50 28.0 ± 14.4 n = 49 31.2 ± 4.3 n = 48 2.28 ± 0.68 n = 48
2.8 ± 3.9 n = 46 1.7 ± 3.4 n = 42 23 ± 24 n = 46 2.1 ± 1.9 n = 46 1.3 ± 1.8 n = 42 18.5 ± 16.3 n = 46 24 ± 37 n = 43 6.4 ± 6.6 n = 43 21.5 ± 16.9 n = 46 4.7 ± 11.1 n = 46 −0.05 ± 3.5 n = 46 0.18 ± 0.48 n = 46
2.4 ± 3.5 n = 42 2.4 ± 3.5 n = 36 13 ± 16 n = 43 1.2 ± 1.3 n = 43 1.0 ± 1.9 n = 36 13.3 ± 15.8 n = 43 16 ± 22 n = 37 4.4 ± 4.3 n = 37 15.6 ± 15.8 n = 43 5.3 ± 12.5 n = 41 0.04 ± 3.1 n = 41 0.13 ± 0.41 n = 41
Treatment effect
P
(95% CI) 0.4 (−1.2 to 2.0)
.62
−0.4 (−2.0 to 1.2)
.61
10 (2 to 19)
b.05
0.9 (0.3 to 1.6)
b.01
0.3 (−0.6 to 1.1)
.52
6.0 (0.2 to 11.7)
b.05
7 (−6 to 19)
.28
1.9 (−0.3 to 4.1)
.09
7.2 (1.6 to 12.7)
b.05
−1.1 (−6.1 to 3.9)
.67
0.3 (−0.9 to 1.6)
.60
0.06 (−0.12 to 0.25)
.50
The changes from 2 to 3 weeks to 6 months were calculated from patients for whom data from both time points were available. Treatment effects and P values were obtained from these data with ANCOVA.
test length of approximately 10 minutes, starting at 25 or 50 W and with a 10-, 25-, or 50-W increase every second minute. Pedaling rate was kept at approximately 60 rotations per minute, and each patient used the same protocol for repeated testing. The flow sensor and the O2 and CO2 sensors were calibrated before each test. Oxygen consumption, carbon dioxide . production (VcO2), and ventilation (VE) were measured on a breath-by-breath basis (MVmax 229, VIASYS Healthcare GmbH, Hoechberg, Germany). All reported values are averaged over 20-second sampling intervals, except for a 30-second sampling interval for the anaerobic threshold (AT). Heart rate was continuously recorded from a 12-lead electrocardiogram, brachial artery blood pressure was measured at the end of each step using an automatic inflatable cuff and a microphone transducer, and exercise time was recorded. . . Maximal VO2 (peak VO2) and the respiratory exchange ratio . . (RER) calculated as VCO2/VO2 were taken at the end of tests. The . AT is given as VO2 at the point where VE begins to increase exponentially for a given increase in oxygen uptake. The AT was determined with the V-slope method when possible; otherwise, . the VE/VO2 method or the point at which a systematic rise in end-tidal oxygen pressure occurs without a decrease in the endtidal carbon dioxide pressure (PETO2) method was used.14 The VE/V̇cO2 slope was determined with the MVmax 229 software plot view function using linear regression of all data obtained during exercise.15 For the oxygen uptake
efficiency slope (OUES),16 data from the second 20-second interval after the start, at the AT, and at peak values were used. The slope calculation option of the Microsoft Excel software (Microsoft, Redmond, WA) was used for calculation of the best-fit linear regression line relating log10VE . and VO2. . Peak heart rate was averaged from the peak VO2 20-second sampling interval. Percentage of heart rate reserve (%HRR) was calculated as ([peak heart rate − resting heart rate]/[220 − age − resting heart rate]) × 100.17 Heart rate recovery was calculated as the difference between peak heart rate and heart rate at 60 seconds after exercise termination. Peak double product (DP) was calculated as peak heart rate × peak systolic blood pressure. Dyspnea was graded according to the New York Heart Association (NYHA) classification system based on standardized interviews at 2 to 3 weeks and at 6 months of follow-up.
Quality of life To assess changes in health-related quality of life, patients answered the Norwegian version 1.2 of the Short Form (SF) 36 questionnaire at 2 to 3 weeks and at 6 months after the infarction. Responses were related at 2 to 3 weeks to the period from primary discharge and at 6 months to the last 4 weeks. Scores18 were weighted and aggregated using normative data from the general Norwegian population19 to
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Figure 1
. Exercise time, peak heart rate, and peak VO2 at 2 to 3 weeks and 6 months after myocardial infarction. In the left panels, solid circles represent the mean values with SD error bars; and thin lines represent the change over time for individual patients. In the right panels, bars represent mean values with SEM error bars.
obtain a physical component summary (PCS) and mental component summary (MCS) score.20 The lowest possible score for both composites is 0; and the highest score is 100, with higher values indicating better health. In the general
population, mean PCS and MCS scores are 50 with SD of 10. A difference of ≥3 points between groups in the change scores (6 months − 2 to 3 weeks) of PCS or MCS was considered to be of clinical significance.20
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Table III. NYHA class mBMC 2-3 wk I II III IV 6m I II III IV Change Improvement ≥1 class Unchanged Worsening ≥1 class
Control
P .33
28 (56%) 18 (45%) 4 (8%) 0
27 (54%) 22 (44%) 1 (2%) 0
37 (74%) 12 (24%) 1 (2%) 0
35 (70%) 14 (28%) 1 (2%) 0
18 (36%) 25 (50%) 7 (14%)
12 (24%) 34 (68%) 4 (8%)
.90
.18
Statistical methods Continuous variables that approximated a normal distribution are presented as mean ± SD, and 2-sample t tests were performed for comparing groups. Treatment effects were calculated with analysis of covariance (ANCOVA), with the baseline value used as a covariate. Continuous variables with a skewed distribution are presented as median (interquartile range). Categorical parameters are presented as frequencies (proportion). Groups were compared with the χ2 test or Fisher exact test as appropriate. The NYHA class change scores (6 months − 2 to 3 weeks) were calculated for testing treatment effects with the χ2 test. All analyses were performed according to the intention-to-treat principle. Twosided tests have been used throughout, and P values b .05 were considered to indicate statistical significance. All statistical analyses were performed with SPSS software version 14.0 (SPSS, Chicago, IL).
Results There were no differences between groups in patient characteristics (Table I). All patients used β-blockers at both time points. During the follow-up period, 24 patients (48%) in the mBMC group and 22 (44%) in the control group followed organized cardiac rehabilitation programs (P = .62 for difference between groups); and 43 (86%) in the mBMC group and 41 (82%) in the control group reported regular individual physical exercise of ≥20 minutes ≥1× per week (P = .56). Of the patients who were smokers at baseline, 13 of 20 in the mBMC group had stopped smoking at 6-month follow-up, compared with 18 of 24 in the control group (P = .47). At 2 to 3 weeks, 47 patients (94%) in the mBMC group and 43 (86%) in the control group underwent exercise testing. At 6 months, the numbers were 49 (98%) and 50 (100%), respectively. The main reason for not performing exercise test at baseline was echocardiographic evidence of left ventricular thrombus (n = 2 in the mBMC group
and n = 7 in the control group). One patient in the mBMC group refused exercise testing.
Functional capacity There were no adverse events in relation to exercise testing, and there were no differences between groups for exercise parameters at 2 to 3 weeks. At 2 to 3 weeks, the RER was 1.13 ± 0.08 in the mBMC group and 1.12 ± 0.07 in the control group (P = .55); at 6 months, it was 1.13 ± 0.07 and 1.12 ± 0.07 (P = .82), respectively. The AT was reached by 42 patients (91%) in the mBMC group and by 39 (91%) in the control group at 2 to 3 weeks (P = 1.00), and by 49 (98%) and 46 (96%), respectively, at 6 months (P = .61). The reason for termination of exercise at 2 to 3 weeks was lower limb pain in 66 patients (73%), dyspnea in 22 (24%), chest pain in 1 (1%), premature ventricular contractions in 1 (1%), and dizziness in 1 (1%). At 6 months, exercise was terminated because of lower limb pain in 85 patients (86%), dyspnea in 12 (12%), and chest paint in 2 (2%). There were no differences between groups for reasons of test termination. There was a significant correlation between the change . in exercise time and the change in peak VO2 in both groups (r = 0.52, P b .001 in the mBMC group; r = 0.37, P b .05 in the control group). At 6 months, there was a . modest increase in peak VO2 and AT in both groups, but without a significant difference between groups (Table II). Exercise time increased significantly more in the mBMC group than in the control group. Time to AT increased similarly in both groups. Peak heart rate and % HRR increased significantly more in the mBMC group than in the control group, and heart rate recovery . increased similarly in both groups. The VCO2 slope was similar in both groups and unchanged from 2 to 3 weeks to 6 months. This was also the case when only data before the AT were used (data not shown). There was a similar modest increase in the OUES in both groups. Individual . responses for exercise time, peak heart rate, and peak VO2 are illustrated in Figure 1. Symptoms There were no differences between groups for the change in symptoms of dyspnea as measured by NYHAclass (Table III). Quality of life The MCS score was mainly unchanged in both groups, whereas there was a similar increase in the PCS score (Table IV). There were no significant differences between groups for the changes in MCS score or PCS score.
Discussions The main finding in this randomized open-labeled study is that patients treated with intracoronary
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Table IV. Quality of life (SF-36) 2-3 wk
PCS MCS
6m
Change
mBMC group
Control group
mBMC group
Control group
mBMC group
Control group
40.9 ± 11.1 n = 37 48.4 ± 10.9 n = 37
42.0 ± 7.4 n = 39 48.2 ± 11.6 n = 39
47.4 ± 8.9 n = 46 51.2 ± 10.7 n = 46
47.7 ± 9.1 n = 45 50.6 ± 8.8 n = 45
5.8 ± 11.2 n = 36 1.2 ± 11.4 n = 36
6.0 ± 9.3 n = 39 2.1 ± 11.9 n = 39
Treatment effect
(95% CI)
P
−0.9 (−4.7 to 2.9)
.66
−0.4 (−4.6 to 3.8)
.86
The change from 2 to 3 weeks to 6 months was calculated from patients for whom data from both time points were available. Treatment effects and P values were obtained from these data with ANCOVA.
injection of autologous mBMCs a few days after anterior wall AMI significantly improved exercise time and heart . rate responses to exercise, but not peak VO2, as compared with the control group. All patients received the best medical treatment. Approximately every second patient followed organized cardiac rehabilitation programs, and this was similar in both groups. We did not find any significant treatment effects for symptoms of heart failure by NYHA class or quality of life assessed by the SF-36 questionnaire. The obvious question to raise is whether the observed improvement in exercise time represents a true treatment effect of intracoronary mBMC injection or a placebo effect. Although excellent correlation between exercise time and oxygen uptake has been demonstrated for bicycle exercise tests, 21 direct measurement of ventilatory gases provides the best validated and most accurate . measure of exercise capacity13; and peak VO2 is a powerful predictor of mortality.8 However, although both β-blockers and angiotensin-converting enzyme (ACE) inhibitors improved prognosis after AMI,12 neither . β-blockers22 nor ACE inhibitors23 improved peak VO2 in patients with heart failure predominately caused by ischemic heart disease. Furthermore, measurement of . peak VO2 is also influenced by patient motivation.24 The similar RER values in the groups at both baseline and 6 months indicate similar effort during exercise. However, the RER is an indirect measurement of the tissue respiratory quotient; and the RER is also influenced by other factors such as hyperventilation.25 Therefore, other indices for accurate measurement of exercise capacity that may be unaffected by patient motivation have been suggested. . Anaerobic threshold correlates well with peak VO226 and can be used as a less effort-dependent measure of exercise capacity.27 We found no indication of a positive effect of mBMC treatment when the AT or the time to AT was measured. However, the use of AT is complicated by methodological issues.14 Because the OUES is linear during exercise, it is a valuable tool for the assessment of exercise capacity . when submaximal levels are reached.16 The VE/VCO2
slope has been most extensively studied as a prognostic marker, but this parameter also correlates with the symptoms and severity of heart failure.28 The similar increase in OUES and the unchanged VE/V̇CO2 slope in the randomized groups from 2 to 3 weeks to 6 months do not support a true treatment effect in the current study. Both peak heart rate and the %HRR increased significantly more in the mBMC group than in the control group, and we also found a trend in favor of the mBMC group for the improvement in the peak DP. The improvement in heart rate response to exercise may indicate a beneficial effect of mBMC treatment. The %HRR is a strong predictor of mortality,17 and heart rate responses to exercise are related to the severity of heart failure.29 Increased peak heart rate may however have been related to patient motivation. Heart rate recovery, on the other hand, reflects vagal activity, is correlated with exercise capacity, and is unrelated to the intensity of exercise.30 Therefore, it may be less influenced by patient motivation. The similar response in heart rate recovery in the randomized groups indicates that the difference in heart rate responses to exercise is mediated by a placebo effect. Compared with similar trials,2,3,5 we injected a smaller number of cells. Because there is no correlation between the number of cells injected and the improvement in cardiac function,2,4,31 too low cell numbers can probably not explain why we did not observe a definite effect on exercise capacity after mBMC treatment. One study suggests that subtle differences in cell preparation may be of importance.32 However, the relevance of differences in in vitro studies and in the mouse hind-limb ischemia model to explain differences between studies of BMC treatment after myocardial infarction in humans remains elusive. More likely, our results confirm the limitations of intracoronary injection of unfractioned BMCs in acute AMI. The BOOST study ended up as a negative study with regard to the primary end point, which was the change in LVEF.6 Janssens et al found that mBMCs reduced infarct size and transiently improved regional
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left ventricular function compared with placebo, but also failed to show an effect on LVEF, which was the primary end point.5 In the REPAIR-AMI study,3 a small treatment effect on the LVEF was observed. Unfortunately, single-plane angiocardiography was used for the assessment of left ventricular function. Because this method is inaccurate in these patients with wall motion abnormalities,33 it is difficult to draw firm conclusions about efficacy from the results of the REPAIR-AMI study.
Study limitations In this open-labeled study, patients in the treatment group may have been more motivated for lifestyle changes. The similar rates for smoking cessation in the groups argue against this. Our results are confined to the methods used and the relatively short observation period of 6 months. A positive treatment effect may potentially be observed after a longer follow-up period. For safety reasons, baseline recordings were obtained 2 to 3 weeks after the acute event; and the absolute values for changes in exercise capacity after AMI may have been underestimated in both groups. Although the ASTAMI study is the second largest study to date on BMC treatment in AMI, it may have been underpowered to . detect small improvements in peak VO2 and quality of life. Conclusions The observed improvement in exercise time after intracoronary injection of autologous mBMCs a few days after AMI may indicate a positive treatment effect, and a possible mechanism is the improvement in the chronotropic response to exercise. However, the mBMC group did not benefit compared with the control group when . the more objective measures such as the peak VO2, AT and . time to AT, heart rate recovery, VE/VCO2 slope, or OUES were used. We are indebted to Lars Gullestad (Department of Cardiology, Rikshospitalet University Hospital), Jostein Hallén (Norwegian School of Sports Sciences), and Per Morten Fredriksen (Department of Physiotherapy, Rikshospitalet University Hospital) for comments on the interpretation of exercise testing and to the staff at the Department of Cardiology at Rikshospitalet University Hospital for assistance during the exercise tests.
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