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European Heart Journal Advance Access originally published online on March 29, 2007
European Heart Journal 2007 28(10):1258-1264; doi:10.1093/eurheartj/ehm011
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© The European Society of Cardiology 2007. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Circulation of CD34+ progenitor cell populations in patients with idiopathic dilated and ischaemic cardiomyopathy (DCM and ICM)

Hans D. Theiss1, Robert David1, Markus G. Engelmann1, Andreas Barth1, Klaus Schotten2, Michael Naebauer1, Bruno Reichart3, Gerhard Steinbeck1 and Wolfgang-M. Franz1,*

1 Medical Department I, Ludwig Maximilians University, Klinikum Grosshadern, Marchioninistr, 15, 81377 Munich, Germany
2 Institute of Medical Informatics, Biometry and Epidemiology (IBE), Ludwig Maximilians University, Klinikum Grosshadern, Munich, Germany
3 Department of Heart Surgery, Ludwig Maximilians University, Klinikum Grosshadern, Munich, Germany

Received 16 May 2006; revised 6 February 2007; accepted 15 February 2007; online publish-ahead-of-print 29 March 2007.

* Corresponding author. Tel: +49 89 7095 6095; fax: +49 89 7095 6094. E-mail address: wolfgang.franz{at}med.uni-muenchen.de

See page 1180 for the editorial comment on this article (doi:10.1093/eurheartj/ehm155)


   Abstract
Top
 Abstract
Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 
Aims: This study aimed at analysing the endogenous stem cell circulation in patients suffering from idiopathic dilated cardiomyopathy (DCM) and ischaemic cardiomyopathy (ICM).

Methods and results: Cytokines in peripheral blood were analysed using enzyme-linked immunosorbent assay and circulating CD34+ stem cell populations (CD34+CD133+, CD34+CD31+, CD34+CXCR-4+) were measured by flow cytometry in DCM patients (n = 25), ICM patients (n = 15), and controls (n = 10). Explanted DCM (n = 5), ICM (n = 4) and normal hearts (n = 5) were analysed for the expression of several homing factors [stromal cell-derived factor-1 (SDF-1), Stem cell factor (SCF), HIF-1a, vascular cell adhesion molecule (VCAM), and Hepatocyte growth factor] by quantitative real-time polymerase chain reaction (PCR). SDF-1 was significantly elevated and positively correlated with brain natriuretic peptide (BNP) in peripheral blood of DCM and ICM patients showing the same New York heart association- (NYHA) class. In DCM patients circulating CD34+ cell populations were significantly increased in comparison to ICM patients and controls. mRNA of SDF-1, SCF, HIF-1a, and VCAM related to glyceraldehyde-3-phosphate dehydrogenase was significantly upregulated in ICM hearts when compared with DCM hearts and controls.

Conclusion: Myocardial homing factors are upregulated in ICM when compared with DCM hearts. Reduced homing of stem cells might therefore explain the increased number of CD34+ cells in DCM patients. These findings may open a new insight into the pathology and the treatment of idiopathic DCM.

Key Words: Dilated cardiomyopathy • Heart failure • Progenitor cell • Stem cell • Mobilization • Homing


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Acknowledgements
 References
 
After myocardial infarction, cytokines like stromal cell-derived factor-1 (SDF-1) are elevated in peripheral blood. These cytokines stimulate the bone marrow resulting in a release of CD34+ progenitor cells into the blood circulation.1 The progenitor cells travel to ischaemic tissue: due to the expression of homing receptors like CXC-chemokine receptor-4 (CXCR-4), they are incorporated via interaction with the corresponding homing factor SDF-1,2,3 which is upregulated immediately after myocardial infarction, and other homing factors like stem cell factor (SCF), HIF-1a, vascular cell adhesion molecule (VCAM), and hepatocyte growth factor (HGF).4–6 In the myocardium, they finally contribute to vasculogenesis and prevent apoptosis.7 In addition, low levels of circulating CD34+ progenitor cells are clinically associated with cardiovascular events and death from cardiovascular causes.8

It is unknown whether this mechanism of progenitor cell circulation also applies to patients with dilated cardiomyopathy (DCM) and ischaemic cardiomyopathy (ICM) who exhibit an increased number of apoptotic cells9 as well as an inhibition of endothelial function.10 Therefore, we analysed several cytokines in peripheral blood and measured different circulating CD34+ cell populations (CD34+ CD133+, CD34+CD31+, CD34+CXCR-4+)1,11,12 in patients suffering from DCM and ICM. CD34+CD133+ and CD34+CD31+ cells represent endothelial progenitor cells (EPCs) in early and late stages of development; CD34+CXCR-4+ cells show the expression of the homing receptor CXCR-4 on CD34+ cells in general. Furthermore, we examined the expression of the homing factors SDF-1 (interacts with CXCR-4), SCF, and HGF (responsible for progenitor cell engraftment),4 VCAM (interacts with VLA-4)6 as well as hypoxia-inducible factor-1 (HIF-1)—a transcription factor that regulates SDF-1 expression5—in explanted DCM, ICM, and control hearts.


   Methods
Top
 Abstract
 Introduction
 Methods
Results
 Discussion
 Acknowledgements
 References
 
Patients
Thirty patients with idiopathic DCM (mean age 52 ± 11 years; 25 men), 15 control subjects (mean age 52 ± 16 years; 11 men), and 19 patients suffering from ICM (mean age 62 ± 12 years; 15 men) were enrolled into the study. Analysis of peripheral blood was performed in 25 DCM patients, 15 ICM patients, and 10 controls. Explanted heart tissue was analysed in another five DCM patients, four ICM patients, and five donor hearts that proved to be unsuitable for transplantation due to palpable coronary calcifications; the latter served as control.

The diagnosis of DCM was based on established criteria.13 Only patients with an angiographic left ventricular ejection fraction (LVEF) <40% were included. Exclusion criteria were coronary artery disease [i.e. no coronary stenosis >30% in coronary angiography and no previous percutaneous coronary intervention (PCI)], significant valvular heart disease, congenital heart disease, active myocarditis, hypertrophic cardiomyopathy with dilative course, alcohol ingestion >100 g/day, and a history of exposure to cardiotoxic drugs. DCM patients showed the following characteristics (mean and standard deviation): NYHA-class 2.8 ± 0.4, ejection fraction 28 ± 7%, end-diastolic volume (EDV) 280 ± 118 mL, and BNP 488 ± 471 pg/mL. DCM patients received standard medical treatment which included ß-blockers (95%), diuretics (90%), angiotensin converting enzyme-inhibitors (ACE-inhibitors) (90%), aspirin (19%), statins (17%), and angiotensin II receptor blockers (10%).

ICM patients had at least one vessel disease with previous PCI. Only patients with an angiographic LVEF <40% were included. Exclusion criteria were acute events like myocardial infarction or PTCA less then 3 months ago and other severe concurrent illness (e.g. active infection, malignancy). ICM patients had the following characteristics: NYHA-class 2.7 ± 0.7, ejection fraction 33 ± 6%, EDV 248 ± 70 mL, and BNP 450 ± 533 pg/mL. They were treated with ß-blockers (95%), diuretics (80%), ACE-inhibitors (70%), aspirin (95%), statins (100%), and angiotensin II receptor blockers (10%).

Control subjects attended the hospital for angina pectoris and were included after exclusion of coronary artery disease by heart catheterization (i.e. no coronary stenosis >30%). They had no other severe concurrent illnesses (e.g. active infection, malignancy, etc.); 70% of controls suffered from arterial hypertension, and 40% from hypercholesterolemia receiving ß-blockers (70%), ACE-inhibitors, angiotensin II receptor blockers (20%), diuretics (10%), and statins (7%).

Initially 48 DCM patients, 27 ICM patients, and 19 controls were assessed for the study. Of these, 14 DCM patients, seven ICM patients, and two controls did not fulfil inclusion criteria or proved to have exclusion criteria. Four DCM patients, one ICM patient, and two controls refused participation in the study.

The study protocol was approved by the institutional committee on human research, and informed consent was obtained from all patients and controls.

Quantification of CD34+ cells
Cytometric analysis was performed using a flow cytometer (FACScan, Becton Dickinson, Heidelberg, Germany) according to ISHAGE guidelines and according to a standard protocol.14 Each analysis included 100 000 events. For immunophenotyping, we used monoclonal antibodies directed against CD31, CD34, CD45, CD133, CXCR4, conjugated with fluorescein isothiocyanate, phycoerythrin, or phycoerythrin cyanine-5 (BD PharMingen/Coulter Immunotech, Hamburg, Germany).

Biochemical measurements
Complete blood count was performed on an automated laboratory cell counter. C-reactive protein was measured by turbidometry (Roche Diagnostics, Mannheim, Germany). Serum levels of interleukin-6 (IL-6), BNP, and tumour necrosis factor-{alpha} (TNF{alpha}) (Biosource Diagnostics, Bruxelles, Belgium) as well as SDF-1, SCF, and VEGF (R&D Systems, Wiesbaden, Germany) were assessed using enzyme-linked immunosorbent assay (ELISA).

Real time polymerase chain reaction
Explanted hearts were selected, if their ‘donors’ fulfilled the criteria for DCM and ICM described above. Only tissue of the left ventricle was used. In ICM heart, the left descending artery showed the leading stenosis as was confirmed by coronary angiography. The quantification of mRNA transcripts of explanted hearts was performed via quantitative real-time reverse transcriptase–polymerase chain reaction (RT–PCR) method. The RNA was prepared with Trizol Reagent (Gibco BRL) from homogenized deep-frozen tissue samples following the TRIZOL standard protocol as described by the manufacturer (GibcoBRL, Eggenstein, Germany). Double-stranded cDNA was synthesized using the superscript double stranded cDNA synthesis kit (Invitrogen, Karlsruhe, Germany). cDNA was amplified and quantified by SYBR Green detection. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) served as an internal control. Thermal cycling and SYBR Green fluorescence detection were done using the Stratagene, MX4000, Multiplex Quantitative PCR System.

Statistical analysis
Results are expressed in mean ± standard deviation as indicated. Comparisons between the three groups were performed by Kruskal–Wallis test (Tables 1 and 2) and Mann–Whitney U test (pairwise, two-sided; Figures 1A, 3A, and 4). A level of P < 0.05 was chosen to indicate statistical significance. Correlation analyses were performed according to Pearson. Statistics were calculated using SPSS for Windows (release 14.0, SPSS Inc., Chicago, IL, USA). Sample size was estimated according to other studies which had similar sample sizes.1,15


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  		Table 1 Study population

 

Figure 1
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  		Figure 1 CD34+-populations in peripheral blood measured by flow cytometry. Histograms show that circulating CD34+CD31+, CD34+133+, and CD34+CXCR-4+ are increased in patients with dilated cardiomyopathy compared with ischaemic cardiomyopathy patients and controls.

 

   Results
Top
 Abstract
 Introduction
 Methods
 Results
Discussion
 Acknowledgements
 References
 
Clinical characteristics
Table 1 reflects the clinical characteristics of our study population. ICM patients were older than DCM patients and controls. However, age showed no significant correlation to the number of progenitor cells in our study population. Gender distribution and the occurrence of atrial fibrillation were similar in all three groups. In comparison to controls, DCM and ICM patients had a significantly lower LVEF and a significantly increased EDV, and they were in a similar NYHA class (2.8 ± 0.4 and 2.7 ± 0.7). ICM patients had more cardiovascular risk factors (CRFs) than DCM patients and controls, and the number of patients on acetyl-salicylic acid and statins was significantly higher in this group; statins had no significant impact on progenitor cell levels, however. Medication concerning ß-blockers, diuretics, ACE-inhibitors, and AT-II-blockers was similar in DCM and ICM patients.

CD34+ cell populations in peripheral blood
Figures 1 and 2A show the amount of circulating CD34+ cell populations measured by flow cytometry. In patients suffering from DCM, CD34+CD31+ (3.6 ± 2.1 vs. 1.9 ± 1.0 cells/µL, P = 0.013), CD34+CD133+ (2.9 ± 1.8 vs. 1.2 ± 0.4 cells/µL, P = 0.009), and CD34+CXCR-4+ cells (1.6 ± 1.1 vs. 0.5 ± 0.3 cells/µL, P = 0.011) were increased in peripheral blood when compared with the control group and with ICM patients (2.2 ± 0.9 cells/µL, P = 0.063; 1.7 ± 0.7 cells/µL, P = 0.022; 0.9 ± 0.3 cells/µL, P = 0.048). CD34+ cells showed no difference between the ICM and control groups. There was no significant correlation between levels of peripheral progenitor cells and NYHA class or BNP (data not shown).

Eight weeks after heart transplantation, levels of CD34+ CD31+-cells decreased in DCM patients (n = 5; 4.7 ± 2.5 vs. 3.0 ± 1.6 cells/µL, Figure 2B). However, these data did not reach significance.


Figure 2
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  		Figure 2 CD34+-populations in peripheral blood measured by flow cytometry.(A) FACS data demonstrate an increased level of CD34+-progenitor cell populations in peripheral blood of dilated cardiomyopathy patients. (B) Histogram shows that number of CD34+CD31+-cells in peripheral blood of dilated cardiomyopathy patients declines after heart transplantation.

 
Plasma levels of cytokines
Plasma levels of SDF-1 and TNF{alpha} analysed by ELISA were significantly elevated in DCM and ICM patients (2560 ± 730 and 2320 ± 490 vs. 1760 ± 410 pg/mL; 2.6 ± 1.0 and 2.7 ± 1.4 vs. 1.3 ± 0.4 pg/dL; P = 0.003 and 0.03, respectively; Table 2and Figure 3A). Serum level of SCF was slightly decreased in DCM patients, whereas levels of VEGF, G-CSF, IL-6, and hs-C-reactive protein did not significantly differ between the three groups (Table 2). BNP was increased both in the DCM and ICM groups (488 ± 471, P = 0.002 and 450 ± 533 pg/mL, P = 0.042) in comparison to controls (14 ± 5 pg/mL). Plasma levels of SDF-1 and BNP (10 DCM and nine ICM patients) were positively correlated (r = 0.71, P = 0.001; Figure 3B).


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  		Table 2 Cytokines in peripheral blood

 

Figure 3
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  		Figure 3 Stromal cell-derived factor-1 and brain natriuretic peptide in serum measured by enzyme-linked immunosorbent assay. (A) Histogram shows the upregulation of Stromal cell-derived factor-1 in serum of dilated cardiomyopathy and ischaemic cardiomyopathy patients. (B) Diagram demonstrates the significant correlation of stromal cell-derived factor-1 and BNP in serum of dilated cardiomyopathy (n = 10) and ischaemic cardiomyopathy (n = 9) patients.

 
Levels of myocardial homing factors
Samples from explanted hearts of five DCM patients, four ICM patients, and five control patients were analysed for SDF-1, SCF, HIF-1a, VCAM, HGF, and GAPDH expression on mRNA level (using quantitative Real Time PCR). In ICM heart, the level of SDF-1 (1.4 x 104 ± 1.4 x 104 relative units vs. 1.4 ± 0.9; P = 0.006), SCF (7.7 x 103 ± 2.2 x 103 vs. 1.1 ± 0.7; P = 0.01), HIF-1a (7.7 x 103 ± 1.6 x 103 vs. 5.4 ± 9.5; P = 0.017), and VCAM (8.1 x 104 ± 3.0 x 104 vs. 32 ± 35; P = 0.006) mRNA—in relation to GAPDH—was significantly higher than in the DCM group (Figure 4). HGF was upregulated in trend (61 ± 41 vs. 2.5 ± 1.7; P = 0.114). Further, the mRNA level of SDF-1, SCF, HIF-1a, and HGF tended to be lower in DCM hearts in comparison to control hearts (4.0 ± 2.4, P = 0.073; 1.4 ± 1.1, P = 0.76; 11 ± 11, P = 0.073; 2.5 ± 1.7, P = 0.19; Figure 4).


Figure 4
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  		Figure 4 Relative amounts of mRNA of stromal cell-derived factor-1, stem cell factor, hypoxia-inducible factor-1a, vascular cell adhesion molecule, and hepatocyte growth factor in heart tissue. Histogram shows the upregulation of myocardial mRNA of stromal cell-derived factor-1, stem cell factor, hypoxia-inducible factor-1a, vascular cell adhesion molecule, and hepatocyte growth factor in relation to glyceraldehyde-3-phosphate dehydrogenase in ischeamic cardiomyopathy patients when compared with dilated cardiomyopathy patients and controls measured by reverse transcriptase–polymerase chain reaction.

 

   Discussion
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
Acknowledgements
 References
 
SDF-1 is known as a potent stimulus of the bone marrow and our data demonstrate that its concentration is elevated and positively correlated to BNP in patients with dilated and ischaemic cardiomyopathy. Furthermore, we found an increased number of circulating cells with stem cell markers in DCM patients—but not in ICM patients and controls. In contrast, essential homing factors like SDF-1, SCF, HIF-1a, and VCAM were significantly upregulated on mRNA level in ICM hearts but not in DCM myocardium and controls. These findings lead us to the hypothesis that in DCM patients endogenous myocardial regeneration via circulating CD34+ cell populations may be impaired by a lack of upregulation of important myocardial homing factors.

There may be several reasons for the increased number of circulating progenitor cells in DCM patients. Today, several cytokines like G-CSF, SCF, VEGF, and SDF-116,17 are known to stimulate bone marrow in response to myocardial ischaemia resulting in a release of progenitor cells into the circulation. In DCM patients, endothelial dysfunction18 and a reduced number of capillaries might trigger the release of progenitor cells from bone marrow via cytokine cascades in a similar way. We showed an increase of circulating SDF-1 (in significant correlation to BNP), and there may be other unidentified circulating factors that lead to a progenitor cell release from bone marrow. There was no significant difference between DCM patients and controls concerning atrial flutter (AF)19 and CRF20 known to influence progenitor cell circulation. Probably, a combination of an elevated SDF-1 in peripheral blood, a lower age in the DCM group compared to ICM patients and a diminution of progenitor cell recruitment to the damaged heart may be responsible for increased circulating progenitor cells in DCM patients.

After heart transplantation for DCM, circulating CD34+ cells show a trend for a decrease in number. As a limitation of the study, we cannot exclude an influence of immunosuppression on this decrease. But our data show that donor hearts express a higher level of several homing factors. It is tempting to speculate that they have a higher capacity to incorporate circulating progenitors because of their slightly increased homing capacity—which may lead to lower progenitor cell levels after heart transplantation. This could indirectly indicate a cause effect relationship between progenitor cell circulation and expression of myocardial homing factors. To directly prove a cause effect relationship between the increased concentration of EPCs and reduced homing factor expression, we would need blood and tissue samples of the same patients.

We also analysed the progenitor cell concentration in ICM patients. They showed a comparable NYHA class, ejection fraction, and EDV of the left ventricle in comparison to the DCM patients. However, ICM patients had normal levels of circulating progenitor cells despite the fact that they showed elevated levels of SDF-1 in peripheral blood. One could argue that ICM patients were older and had more statin therapy than DCM patients. However, age and statin therapy had no significant impact on our results. As statin therapy has been described to increase progenitor cell levels,21 the ‘real’ difference between DCM and ICM may even be higher without influence of statins. Therefore, the normal progenitor level in peripheral blood of ICM patients might be due to the increased expression of homing factors in ICM hearts.

In contrast to a recent publication by Valgimigli et al.,22 we did not observe a correlation between mobilization of CD34+ cells, levels of TNF{alpha}, and NYHA classification. Furthermore, these authors found no role for the aetiology of cardiomyopathy. This may be due to the fact that our study population is more homogenous. We included DCM and ICM patients in NYHA classes II or III only, and excluded heart disease due to hypertension, valvular disorders, myocarditis, and congenital disorder. Whatever the reason may be, there exist some obvious contradictions between the two publications that have to be resolved in further studies. Nevertheless, we believe that the level of myocardial homing factors has important influence on circulating progenitor cell levels.

In contrast to DCM and controls, important homing factors like SDF-1, SCF, HIF-1a, and VCAM were significantly upregulated on mRNA level in ICM hearts. We measured all homing factors in relation to GAPDH, which is expressed ubiquitously in all cells because we expected the architecture of DCM, ICM, and control hearts to be different in regard to concentration of collagen, myocytes, and non-myocytes. Possibly, this downregulation of several homing factors impairs the migration of circulating progenitor cells into the DCM heart and thus contributes besides other factors like elevated SDF-1 to an increased amount of circulating progenitor cells in these patients. An inefficient incorporation of progenitor cells into DCM hearts could finally cause an increased apoptosis of local cardiomyocytes.7 A knock-out animal model and cardiac FACS will be used in order to study trafficking of circulating progenitor cells to finally prove our hypothesis of impaired homing.

Our study is limited by a small sample size as well as differences in the study population (see Table 1). Furthermore, there are limitations regarding the analysis of the myocardial homing factors utilizing a random sample of tissue from a heterogeneous myocardium. Nevertheless, our findings may have immediate consequences on progenitor cell therapy in patients suffering from heart failure. Intracoronary infusion of progenitor cells seems to improve outcome of ICM patients23,24—maybe because of the increased myocardial homing capacity. Possibly, DCM hearts may respond less to progenitor cell mobilization or transfusion as suggested by a recent pilot study.25 Therefore, new therapeutic options providing homing factors to the apoptotic myocardium may become necessary for the treatment of DCM patients. Tomita et al.26 showed in a mouse model that G-CSF administration leads to increased incorporation of bone-marrow cells into doxorubicin-induced cardiomyopathic hearts. It is conceivable that G-CSF administration might enhance the homing capacity of cardiomyopathic hearts in addition to progenitor cell mobilization. Furthermore, transcription factors such as HIF-1 could be an interesting target to eventually increase the expression of homing factors in DCM hearts. Providing a conductive environment for efficient homing of circulating CD34+ cells may therefore become a promising new treatment option for patients suffering from DCM.


   Acknowledgements
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
References
 
We thank J. Arcifa and A. Schroff for excellent technical assistance. Furthermore, we thank H. Diem, MD, and M. Adam, MD, Institute of Clinical Chemistry, Ludwig Maximilians University, for great support with flow cytometry analyses. This work was supported by grants from the ‘Fritz-Bender-Foundation’, Munich, ‘Dr Helmut Legerlotz-Stiftung’, Weitnau, and MSD Sharp&Dohme, Munich, all Germany.

Conflict of interest: none declared.


   References
Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 Acknowledgements
 References
 

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