Intracoronary Infusion of Autologous Bone Marrow Cells for Treatment of Idiopathic Dilated Cardiomyopathy

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Brief Title

Intracoronary Infusion of Autologous Bone Marrow Cells for Treatment of Idiopathic Dilated Cardiomyopathy

Official Title

Effects of Intracoronary Infusion of Bone Marrow-derived Progenitor Cells on Myocardial Regeneration in Patients With Non-ischemic Dilated Cardiomyopathy.

Brief Summary

      The main aim of the study is to determine whether intracoronary infusion of autologous bone
      marrow mononuclear cells can improve the ventricular function of patients with idiopathic
      dilated cardiomyopathy.Secondary end-points will be:

        1. To evaluate possible changes in patient functional capacity and

        2. to identify the biological characteristics of the bone marrow graft that might influence
           on functional recovery.
    

Detailed Description

      Clinical studies have shown that bone marrow cells can regenerate damaged myocardium after
      ischemic cardiopathy; however scarce information is available from patients with non-ischemic
      dilated cardiomyopathy. The aim of the present work is to investigate the role of
      intracoronary infusion of autologous marrow-derived stem cells in a phase II study in 30
      patients with dilated cardiomyopathy.Before the intracoronary transplant of marrow cells as
      well as six and twelve months thereafter, we will compare the ventricular function measured
      as left-ventricular ejection fraction by angiography, magnetic resonance imaging,
      echocardiography and treadmill direct oxygen consumption test. Functional capacity will be
      monitored throughout the study. In every condition of the study we will perform at least one
      30º right anterior oblique left ventricle (LV)angiogram. During each ventriculogram, attempts
      will be made to obtain a sinus and a post-extrasystolic beat for analysis, in order to study
      contractile reserve behaviours. Post-extrasystolic beats will be obtained by inducing
      premature beats with the catheter, once a well opacified cardiac cycle with a normal sinus
      beat had been filmed. In all instances, the r-r' interval of the induced premature beat and
      the post-extrasystolic pause will be recorded and measured.

      Measurements and calculations will be made off line in our own core lab, where end-diastolic
      and end-systolic silhouettes were drawn using the CASS system by 2 expert angiographers who
      were unaware of the patient group or study conditions. LV-volumes and ejection fraction (EF)
      were derived and regional wall motion was analyzed. The method by Sheehan (1) was used for
      the asynergy study, dividing the superimposed silhouettes in 100 radii of wall shortening,
      from end-diastole to end-systole. The abnormal contracting segment (ACS) was defined as the
      percentage of radii showing akinesia or dyskinesia. The areas of the ventrivular walls having
      asynergy will be regionally evaluated. The serial evolution of the contractile reserve will
      be evaluated by the post-extrasystolic potentiation.

      Coronary Flow Reserve (CFR) in all 3 coronary arteries will also be evaluated during every
      hemodynamic study (before treatment and 6 months after treatment). The FloMap® system
      (Cardiometrics; Mountain View; California) will be used. A 0.014" intracoronary Doppler guide
      wire will be positioned proximally in every coronary and flow velocities will be recorded
      continuously. Average peak velocity will be obtained at baseline and after an intracoronary
      bolus of Adenosine. CFR will be calculated as the ratio between maximal flow velocity during
      the peak effect of the adenosine injection and basal flow velocity.

      Magnetic Resonance Image (MRI) studies will be performed in 3 conditions (baseline, 3-month
      and 1-year after treatment). Functional parameters will be obtained in each condition,
      including LV-volumes, LV-mass and ejection fraction

      On the morning of cardiac catheterization, up to a volume of 100-150 ml of marrow will be
      obtained under local anesthesia by aspiration from the iliac crest. Mononuclear Bone Marrow
      Cells (MNBMCs) will be isolated by density gradient centrifugation over Ficoll-Hypaque
      technique in a sterile, semiautomated device COBE® 2991. After three washes, MNBMCs will be
      filtered and resuspended in 10 ml of 0.9% sodium chloride supplemented with preservative-free
      0.1% heparin. Aliquots will be obtained for cell count as well as for cytofluorometric and
      functional analyses of the cell content.

      Cells will be directly transferred to all 3 coronary arteries (50% to left anterior
      descending artery, 25% to the circumflex and 25% to the right coronary artery) by the use of
      a coaxial balloon catheter, which will be placed proximally at each artery. Balloon size will
      be selected according to vessel size, in order to achieve complete occlusion of the vessel
      and to stop flow during cell injection. So, backflow of cells is prevented and distal
      stagnant flow will facilitate cell exposure. The cell suspension will be injected through the
      distal tip of the balloon over 2 to 4 minutes.

      In addition,we will try to compare all possible changes in functional parameters with
      biological variables obtained from the marrow graft, such as:

        1. Number of cells positive for cluster of differentiation antigen (CD) CD146,CD31,
           CD133,CD90,CD38, CD117, CD73, CD105, CD45, Vascular endothelial growth factor receptor
           2,CXC-chemokine receptor 4 and HLA-DR.

        2. Functional characterization of endothelial progenitor cells and mesenchymal stem cells
           present in the graft by in vitro selective cultures.

        3. Analysis of the in vitro chemotactic ability of the infused cells.

        4. Determination of lineage-specific cardiac markers GATA-4 and Nk2.5/Csx in the infused
           marrow-derived cells. Correlations between these biological parameters and the effects
           on patient`s ventricular function could highlight the role of each of the potential
           mechanisms implied in cell-mediated myocardial regeneration.
    

Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Improvement of left ventricular function

Secondary Outcome

 Functional status

Condition

Dilated Cardiomyopathy

Intervention

Intracoronary infusion of autologous bone marrow cells

Study Arms / Comparison Groups

 1
Description:  All included patients are assigned to arm 1, in which they are treated by the intervention

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Procedure

Estimated Enrollment

27

Start Date

February 2008

Completion Date

December 2010

Primary Completion Date

August 2010

Eligibility Criteria

        Inclusion Criteria:

          1. Patients of both genders with established clinical and angiographic diagnosis of
             Idiopathic Dilated Cardiomyopathy who accept to participate in the trial.

          2. They should have symptoms and/or signs of heart failure, despite optimized medical
             treatment.

          3. Angiographic ejection fraction should be less than 50%.

        Exclusion Criteria:

          1. Associated coronary artery disease.

          2. Any history or suspicion of a toxic, pharmacologic or deposit etiology.

          3. Absence of resynchronization therapy.

          4. Age longer than 80 years.

          5. Associated malignant or pre-malignant systemic disease.

          6. Associated hematologic disorder.
      

Gender

All

Ages

18 Years - 80 Years

Accepts Healthy Volunteers

No

Contacts

Jose Suarez de Lezo, MD, PhD, , 

Location Countries

Spain

Location Countries

Spain

Administrative Informations


NCT ID

NCT00629096

Organization ID

TCMR0007/2006

Secondary IDs

EudraCT 2007-003088-36

Responsible Party

Sponsor

Study Sponsor

Fundación Pública Andaluza Progreso y Salud

Collaborators

 Iniciativa Andaluza en Terapias Avanzadas

Study Sponsor

Jose Suarez de Lezo, MD, PhD, Study Chair, Department of Cardiology. Reina Sofía University Hospital


Verification Date

May 2013