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European Journal of Heart Failure 2008 10(7):661-667; doi:10.1016/j.ejheart.2008.05.010
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© 2008 European Society of Cardiology

Effect of repeated intracoronary injection of bone marrow cells in patients with ischaemic heart failure The Danish Stem Cell study—Congestive Heart Failure trial (DanCell-CHF)

Axel C.P. Diederichsena,*, Jacob E. Møllera, Per Thayssena, Anders B. Junkera, Lars Videbæka, Susanne G. Sækmoseb, Torben Baringtonb, Malthe Kristiansenc and Moustapha Kassemc

a Department of Cardiology, Odense University Hospital Denmark
b Department of Clinical Immunology, Odense University Hospital Denmark
c Department of Endocrinology and Metabolism, Odense University Hospital Denmark

* Corresponding author. Department of Cardiology, Sdr. Boulevard 29, Odense University Hospital, DK-5000 Odense C, Denmark. Tel.: +45 65412627; fax: +45 63120854. E-mail address: a.diederichsen{at}dadlnet.dk (A.C.P. Diederichsen).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: It has been suggested that myocardial regeneration may be achieved by a single intracoronary bone marrow derived stem cell infusion in selected patients with ischaemic heart disease. The effect is uncertain in patients with chronic ischaemic heart failure and it is not known whether repeated infusions would have additional positive effects.

Aims: To assess whether two treatments of intracoronary infusion of bone marrow stem cells, administered 4 months apart, could improve left ventricular (LV) systolic function in patients with chronic ischaemic heart failure.

Methods: The study was prospective and non-randomised, comprising an observational baseline period of 4 months followed by an interventional period of 12 months. Intracoronary bone marrow cell infusion was performed at the end of the baseline period and repeated 4 months later.

Results: 32 patients were included. LV ejection fraction remained unchanged (33±9% vs. 34±10% after 8 months, p=0.30). Likewise, there was no significant change in LV end-systolic volume, wall motion score index (WMSI) or contractile reserve. At 12 months, a decrease in target vessel WMSI was seen (2.17±0.34 vs. 2.06±0.46, p=0.02). Furthermore, NYHA class improved (p<0.0001). No deaths were observed.

Conclusion: In this non-randomised study, no change in LV ejection fraction could be demonstrated after repeated intracoronary bone marrow stem cell treatment in patients with chronic ischaemic heart failure.

Key Words: Ischaemic heart failure • Stem cell therapy • Left ventricular ejection fraction

Received January 30, 2008; Revised April 7, 2008; Accepted May 15, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Despite aggressive therapeutic interventions the mortality and morbidity of acute and chronic ischaemic heart failure remain high. One of the fundamental pathophysiological problems in the management of these patients is irreversible myocardial damage induced by myocardial ischaemia. Experimental studies have suggested that progenitor cells from the bone marrow may possess an ability to induce neoangiogenesis and myocardial regeneration [1]. Encouraged by these results, the effect of autologous bone marrow stem cell treatment has been investigated in several clinical trials [2-4]. These studies have demonstrated the feasibility and safety of the intervention. Although initial results of intracoronary infusion of bone marrow cells in patients with acute myocardial infarction (AMI) has demonstrated a beneficial effect on left ventricular (LV) systolic function [2], the results of larger clinical trials have been conflicting [3,4]. In the setting of chronic ischaemic heart disease, there are limited published data on the effect of autologous bone marrow stem cell treatment [5]. In a recent study, one treatment with intracoronary injection of bone marrow derived stem cells was associated with a statistically significant improvement in LV ejection fraction (LVEF) 3 months after infusion [6]. Although encouraging, it is not known whether this effect on LV function is sustained over time. Furthermore, it is not known whether repeated cell infusions possess an additive beneficial effect.

The objective of the present study was therefore to assess the effect of two treatments with intracoronary infusion of bone marrow cells, administered 4 months apart, on LV systolic function and functional status in patients with chronic ischaemic heart failure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Patients
87 patients with symptomatic ischaemic heart disease were screened for inclusion in the study between September 2005 and February 2006. Inclusion criteria were: stable, symptomatic (New York Heart Association (NYHA) functional class II / III and/or Canadian Heart Association Classification of Angina (CCS) class II / III), aged 18-75 years, with known depressed LV systolic function (LVEF <45%), on optimal medical therapy and not amenable for further coronary revascularisation. Exclusion criteria were: non-cardiac serious diseases expected to reduce the patient's short-term survival, recent (<6 months) myocardial infarction, permanent atrial fibrillation or implanted pacemaker. Of the 87 screened patients, 14 patients were mildly symptomatic, 13 had preserved systolic function, 8 had a serious comorbidity, and 17 patients were unwilling to participate. The remaining 35 patients were included in the study. Three patients did not complete the protocol, one patient died before the first treatment, one patient withdrew consent, and one patient experienced an iatrogenic dissection of the right coronary artery during the first pre-treatment coronary angiography. The remaining 32 patients completed the study.

The protocol was approved by the Regional Scientific Ethical Committee for Southern Denmark (VF-20050025); the study was registered at ClinicalTrials.gov (NCT00235417 [ClinicalTrials.gov] ) and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from each patient.

2.2. Study design
The study was prospective, open-labelled and non-randomised. An observational baseline period of 4 months with three outpatient visits, was followed by an interventional period of 12 months (Fig. 1). Each patient was scheduled to receive two treatments with intracoronary infusion of autologous bone marrow stem cells, administered 4-months apart. Outpatient follow-up was performed 4, 8 and 12 months after the first infusion.


Figure 01
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  		Fig. 1 Scheduled study investigations. BMC denotes bone marrow cell; Echo denotes contrast enhanced echocardiography; LDDE denotes low dose dobutamine echocardiography; CATH denotes coronary angiography.

 
The primary endpoint was change in LVEF, from the mean of the three baseline assessments to 8 months after the first cell infusion, measured with quantitative 2 dimensional (2D) contrast echocardiography. Secondary endpoints were: change in 1) LV end-systolic volume (LVESV) 2) regional LV function 3) extent of myocardial viability 4) contractile reserve and 5) exercise capacity on bicycle exercise test. Tertiary endpoints were changes in NYHA and CCS classifications.

2.3. Echocardiography
A comprehensive quantitative transthoracic contrast enhanced echocardiography was performed at each visit by a single observer. All images were stored digitally for subsequent offline analysis which was done blinded for patient data and timing of echocardiography.

LV systolic function was assessed according to the recommendations of the American Society of Echocardiography [7]. LV chamber opacification was enhanced in all patients using a transpulmonary contrast agent (SonoVue®, Bracco). From the apical 2- and 4-chamber views, LV volumes and LVEF were estimated using biplane planimetry. From multiple short axis views, apical 2-, 4-, and long axis views, a wall motion score index (WMSI) was obtained by dividing the left ventricle into 16 segments. Each of the segments was assigned a score based on myocardial thickening. WMSI was calculated by dividing the sum of scores by the number of segments visualised. Three myocardial regions were constructed according to the major coronary arterial territories [7]. At baseline, the presence of myocardial viability was assessed in order to detect the target vessel for administration of bone marrow stem cells. At baseline and after 4 and 8 months a low dose dobutamine contrast echocardiogram was performed in order to assess contractile reserve. During continuous ECG monitoring, dobutamine was infused at doses of 5 and 10 µg/kg/min, for 3 min of each dose. Myocardial viability was defined as an improvement of ≥1 in the scoring of ≥1 myocardial segments during dobutamine infusion compared with wall motion at rest. Contrast enhanced images were obtained at baseline and at the end of the dobutamine infusion.

Interobserver variability was assessed by reanalysis of 50 randomly selected echocardiograms by an independent observer with no other participation in the study. Mean percent error of assessment of LVEF was 4±13% and of WMSI 4±8%, corresponding to a mean absolute difference in LVEF of 1.6 percent points, and an absolute difference in WMSI of 0.08 units. The interobserver correlation coefficient for LVEF was 0.95 and 0.94 of WMSI.

2.4. Exercise test
To assess exercise capacity a maximal symptom limited bicycle ergometer test was performed. Initial loading was 25 W increasing by 25 W every 2 min with continuous ECG monitoring. Endpoints for termination of the test included a drop in systolic blood pressure >10 mm Hg from baseline blood pressure, moderate or severe angina, ventricular tachycardia, ST segment elevation >1 mm in leads without Q waves, or inability to continue exercise.

2.5. Preparation, characterisation and intracoronary infusion of bone marrow cells
On the day of cell therapy, bone marrow was aspirated (up to 174 ml) under local anaesthesia from the iliac crest, and resuspended with Heparin (2500 IE/ml). Bone marrow mononuclear cells were isolated by Lymphoprep (Axis-shield, Norway) density-gradient centrifugation, washed twice and finally resuspended in 30 ml commercially available, approved for human use, sterile 5% human Albumin (ZLB, Switzerland) supplemented with 20 IU/ml Heparin. Of the final preparation, 1 ml was used for cell count with an automated haemocytometer (Sysmex) and 1 ml was examined using flow cytometry. For flow cytometry the isolated cell populations were stained using the following conjugates: Anti-CD45 PE-Cy5 (DakoCytomation, clone T29/33), anti-CD34 FITC (Becton Dickinson, clone 8G12), anti-CD133 PE (Miltenyi Biotec, clone AC133) and propidium iodide. Acquisition was performed on a FACS Calibur and subsequent data analysis was carried out with CellQuest 3.3 software (Becton Dickinson) (Fig. 2). Cells were infused within 7 h of bone marrow aspiration.


Figure 02
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  		Fig. 2 Flow cytometry: (A) A CD45/SSc dotplot was used to define the leucocyte population as CD45+ events (R2). (B) In the leucocyte population (R2) stem cells were defined as CD34+ SSc lo events in a CD34/SSc dotplot. For this particular patient the CD34 positive cells comprised 1.4% of the leucocyte population (R3). (C) The fraction of CD133+ CD34+ stem cells was estimated using a CD34/CD133 dotplot. In the patient shown here, this population comprised 58% of the CD34 positive cell population.

 
Intracoronary cell infusion was done using the stop-flow technique, with an over-the-wire balloon catheter placed in the target vessel supplying the area with the most extensive regional wall motion abnormalities avoiding areas with aneurisms. The balloon was inflated for 2 min, while 5 ml of the cell suspension was infused distally into the vessel. This was repeated 4 times, interrupted by 3 min of reflow.

2.6. Safety and feasibility
Troponin T and creatine kinase MB were measured prior to bone marrow aspiration, prior to cell infusion and repeated 8 and 16 h after infusion. The patients were observed over 24 h for arrhythmias before discharge. To evaluate possible microbial contamination of the cell suspension, 1 ml of the final cell preparation was used for microbiological culture (BactAlert). Clinical follow-up was performed by a physician at discharge and 4, 8 and 12 months after the first treatment. Possible procedural complications and any clinical events (deaths or hospitalisations) were recorded.

2.7. Statistical analysis
Sample size estimation was based on an expected mean LVEF of 30% in the studied population (standard deviation of 8%). A clinically relevant increase in LVEF was chosen to be at least 5%. A standard error of 2% was expected at each assessment of LVEF (the standard error of the mean of three baseline studies estimated to 1%). Given these assumptions to detect a true increase in LVEF of 5% with a standard deviation of 10% and a power of 80%, a sample size of 35 patients was required.

Continuous variables are presented as mean±standard deviation. Within patient change in outcome measures from mean of baseline investigations to 8 months after cell infusion were assessed with paired t-test. Overall within subject changes of continuous variables were assessed with unbalanced repeated measures analysis of variance with Bonferroni corrected post hoc tests. A p-value <0.05 was considered significant. SPSS version 15.0 (SPSS Inc. Chicago, Illinois) was used for statistical analyses.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
Demographic and clinical characteristics of the 32 patients that completed the study are summarised in Table 1. Prior to therapy, 10 patients were in NYHA class II, 20 in class III and none in class IV. Two patients only had angina, CCS class II. Target vessels were: left anterior descending artery (n=21), left circumflex artery (n=4), and right coronary artery (n=9). At the first treatment a mean of 139 ml bone marrow was aspirated, and we infused a mean of 647±382x106 cells with an average of 9.7±6.3x106 CD34+-cells of which 5.1±3.0x106 were also CD133+. At the second treatment a mean of 163 ml bone marrow was aspirated, and we infused a mean of 889±361x106 cells with an average of 14.1±7.3x106 CD34+-cells of which 8.5±4.2x106 were also CD133+. The viability of the cells was above 98% at the time of infusion. Within 3 months of the first infusion, 4 patients underwent concomitant percutaneous coronary intervention; no patients underwent CABG during the study.


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  		Table 1 Baseline characteristics of the patients (n=32)

 
3.1. Left ventricular function
LVEF remained unchanged over the observational period (p=0.75). The mean of the three baseline measurements of LVEF was 33% with a standard error of 1.4%. With cell infusion no change in LVEF was seen either at the first or repeated infusion (Table 2). At 8 months (primary endpoint) the change in LVEF from baseline was a non-significant increase of 1.1±5.5% points (p=0.30) and furthermore there was no difference whether the target vessel was a genuine coronary vessel (n=22) or a coronary artery bypass graft (n=10). Likewise no significant change in LVESV was found (Table 2). Overall no significant improvement in WMSI was found (p=0.28). However a trend towards an improvement in regional wall motion was seen although this was only significant (p=0.02) from baseline to 12 months (Table 2). By low dose dobutamine echocardiography there were no changes in WMSI, regional wall motion or contractile reserve after cell infusion (Table 2).


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  		Table 2 LV function and exercise capacity at baseline and after BMC infusion

 
The change in LVEF from baseline to 8 months did not correlate with total amount of CD34+ infused at the two treatments (r=0.19, p=0.34) or CD133+ cells (r=0.24, p=0.19). The same was the case at 12 months (CD34+ r=–0.11, p=0.56; CD133+ r=–0.03, p=0.89). Also no correlation between change in WMSI and total number of cells at 8 months (CD34+ r=0.03, p=0.89; CD133+ r=0.18, p=0.37) or 12 months (r=0.19, p=0.32; r=0.02, p=0.92) was found.

3.2. Exercise test and functional status
Although exercise capacity on ergometer test improved initially and significantly after 8 months (Table 2), this effect was not sustained at 12 months. Despite this, a sustained symptomatic improvement was achieved with a sustained decrease in NYHA functional class (p<0.0001: Table 2). The CCS class remained unchanged from 1.2±0.5 (mean of the three baseline estimations) to 1.1±0.3, 1.0±0.2 and 1.1±0.2 (at 4, 8 and 12 months after the first treatment).

3.3. Adverse events and clinical endpoints
Intracoronary cell infusion did not result in elevation of creatine kinase MB or troponin T, in addition no arrhythmias occurred. All patients were discharged as scheduled the day after cell infusion. Four months after the second stem cell infusion no patients had developed angiographic restenosis or de novo stenosis.

Within the 12 month follow-up period after first treatment, there were no deaths, AMIs or strokes. 12 patients (37%) were rehospitalised a total of 25 times due to worsening heart failure (n=2), worsening angina (n=7), need for additional revascularisation (n=1), atrial fibrillation (n=3), second-degree AV-block (n=1), syncope (n=1), intraventricular mural thrombus (n=1) and various non-cardiac reasons (n=9). For comparison, in the year prior to inclusion in the study 16 patients (50%) were hospitalised for various reasons. During 12 months of follow-up, no development of neoplasia or retinopathy was observed.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
The present non-randomised study demonstrates that repeated intracoronary bone marrow cell infusions are feasible in a population with severe ischaemic heart disease and depressed LV systolic function. Although this was associated with a symptomatic relief and transiently improved exercise capacity we were unable to detect any improvement in LVEF or in WMSI.

Traditionally, protection of non-damaged myocardium and attenuation of ischaemic damage has a pivotal role in the management of patients with acute and chronic ischaemic heart disease. Use of stem cells in the treatment of AMI has raised hopes for a new therapy with the ability to protect the myocardium against cell death, but results have been conflicting. In some studies, LVEF has been shown to increase [2,4,8]; although in one study the effect was not sustained with extended follow-up [9]; and in other studies LVEF remained unchanged [3,10]. A very recent meta-analysis concluded that intracoronary cell therapy following percutaneous coronary intervention for AMI appeared to provide statistically and clinically relevant benefits on cardiac function and remodelling [11].

Currently there are no established treatment modalities that can repair damaged ischaemic tissue and restore its contractile function. Recently, use of stem cells in the treatment of ischaemic myocardium, with the aim of inducing regeneration and neoangiogenesis, has raised hope for a therapy with the ability to restore cardiac function [6,12,13]. In contrast to these studies, the present study did not show any significant improvement in LV systolic function. In a randomised cross over study of 75 patients with chronic ischaemic heart disease (LVEF 41%), Assmus et al. reported a mean increase in LVEF of 2.9%, 3 months after a single treatment with bone marrow stem cells [6]. LVEF was assessed using quantitative LV angiography. In our study, despite two sequential treatments and infusion of a considerably larger amount of bone marrow cells (3 and 5 times more cells at the first and second treatments respectively) as well as CD34+ cells (5 and 7 times more cells at the first and second treatments respectively) and 12 months of follow-up, LVEF was unchanged in both the observational and the interventional period. We used contrast enhanced echocardiography for the assessment of LVEF. Enhanced echocardiography has a low variability [14,15], and a reproducibility at least as good as angiographic assessment of LVEF [16]. Furthermore, the number of concomitant percutaneous coronary interventions was different in the two study populations, 38% in the study of Assmus et al. and in 9% in our study.

In accordance with others [5], we observed an improvement in functional status. It is noteworthy, that despite an unchanged LVEF no major cardiac events (deaths or AMI) were observed within 12 months of follow-up in a population with an expected annual mortality rate of 10-15%. This might suggest that LVEF is a poor marker for outcome of stem cell therapy.

An important limitation for evaluating the efficacy of stem cell therapy and comparing different studies is the fact that a mixture of bone marrow derived stem cells has been employed. Traditionally, it has been generally accepted that endothelial progenitor cells express CD34 and are resident in bone marrow. However, apart from CD34+-cells, the bone marrow contains a variety of other stem cells. Thus CD133 has been established as a marker for the very early endothelial progenitor cells, being able to differentiate into endothelial cells in vitro [17], and forming the neointima in vivo [18].,The ability of CD133+-cells to improve myocardial function has recently been demonstrated in a clinical trial [19]. Although the observed CD34+and CD133+ cell counts were very high in our study, they were not predictive for a positive outcome. This is in concordance with a recent meta-analysis which concluded that there was no dose-response relationship between the number of injected cells and the LVEF change in AMI patients [11]. Also ex vivo conditions, timing of treatment and route of delivery may account for the conflicting results of stem cell therapy [20].

Our study has several limitations. The present study is not randomised or placebo controlled. Although all echocardiography measurements were carried out without any knowledge of clinical conditions, a risk of bias is present. Further, the sample size is small with the potential risk of a type 2 error. However, with the observed LVEF and standard error at baseline we possess adequate power to detect a true difference in LVEF of 5% with a power of 80% and the data suggest no trend towards an increase of LVEF.

Even though this study comprised an observational baseline period of 4 months followed by an interventional period, the study is non-randomised, and one should be careful when drawing conclusions. However, the present study did not demonstrate any improvement in LV systolic function after two sequential treatments with intracoronary infusion of bone marrow cells in patients with chronic ischaemic heart failure. The treatment was safe and associated with clinical improvement. Until now only a few studies have been reported on bone marrow stem cell therapy in chronic coronary disease and the results are conflicting. In conclusion, this treatment strategy is still controversial, and many issues remain unanswered. Thus further randomised, placebo controlled studies are warranted, preferably with clinical endpoints such as mortality and morbidity rather than LVEF.


   Acknowledgements
 
We are indebted to Karsten Tange Veien MD, Odense University Hospital for assistance in the assessment of interobserver variability of outcome measures, Professor Werner Vach Department of Statistics University of Southern Denmark for statistical advice and sample size estimation, and special thanks to the dedicated nursing and technical staff at the heart failure clinic, the cardiac catheterisation laboratory, the coronary care unit and the Department of Clinical Immunology of Odense University Hospital.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

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  9. Meyer G.P., Wollert K.C., 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) 113:1287–1294.[Abstract/Free Full Text]
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