Dilated Cardiomyopathy
Conditions
Keywords
Stem Cells, Heart Failure, Dilated Cardiomyopathy
Brief summary
Several studies have documented that transplantation of bone marrow-derived cells (BMC) following acute myocardial infarction is associated with a reduction in infarct scar size and improvements in left ventricular function and perfusion. The available evidence in humans suggests that BMC transplantation is associated with improvements in physiologic and anatomic parameters in both acute myocardial infarction and chronic ischemic heart disease, above and beyond the conventional therapy. In particular, intracoronary application of BMC is proved to be safe and was associated with significant improvement in the left ventricular ejection fraction (LVEF) in patients with chronic heart failure. In contrast to ischemic heart failure, the data on effects of BMC transplantation in patients with dilated cardiomyopathy are limited to pre-clinical studies. In a rat model of dilated cardiomyopathy, intramyocardial delivery of pluripotent mesenchymal cells improved LVEF, possibly through induction of myogenesis and angiogenesis, as well as by inhibition of myocardial fibrosis, suggesting that the beneficial effects of stem cell transplantation in dilated cardiomyopathy may primarily be related to their ability to supply large amounts of angiogenic, antiapoptotic, and mitogenic factors. Similarly, transplantation of cocultured mesenchymal stem cells and skeletal myoblasts was shown to improve LVEF in a murine model of Chagas disease. Study Aim: To define the clinical effects of BMC transplantation in dilated cardiomyopathy in a pilot clinical study investigating the effects of intracoronary CD34+ cell transplantation on functional, structural, neurohormonal, and electrophysiologic parameters in patients with end-stage dilated cardiomyopathy.
Detailed description
Patients were randomly allocated in a 1:1 ratio to receive intracoronary transplantation of autologous CD34+ stem cells (SC group) or no intracoronary infusion (control group). At the time of enrollment, and at yearly intervals thereafter, we performed detailed clinical evaluation, echocardiography, 6-minute walk test, and measured plasma levels of NT-proBNP. To better-define the potential role of inflammatory response, we also measured plasma inflammatory markers (tumor necrosis factor \[TNF\]-α and interleukin \[IL\]-6) at the time of CD34+ stem cell injection.
Interventions
BIOLOGICALCD34+ autologous stem cell transplantation
Peripheral blood stem cells will be mobilized by daily subcutaneous injections of filgrastim; CD34+ cells will be collected via apheresis and labeled with technetium. Patients will undergo myocardial perfusion scintigraphy for myocardial viability assessment and the collected CD34+ cells will be injected intracoronary in the artery supplying the segments of reduced tracer accumulation
Patients will undergo filgrastim stimulation and viability assessment using the same protocol as in Arm 1. However, in this group, no intracoronary stem cell delivery will be performed; the patients will receive placebo (saline).
BIOLOGICALSC therapy
In the SC group, CD34+ cells were mobilized by granulocyte colony-stimulating factor and collected via apheresis. Patients underwent myocardial scintigraphy and cells were injected in the artery supplying segments with the greatest perfusion defect
Sponsors
Blood Transfusion Centre of Slovenia
Stanford University
University Medical Centre Ljubljana
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Normal coronary angiogram * Left ventricular ejection fraction \< 40% * NYHA III or IV heart failure symptoms * Bone marrow reactivity (G-CSF test) * Presence of viable myocardium
Exclusion criteria
* Hematologic malignancy * Multiorgan failure
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Heart Failure Mortality | 5 years | — |
| Changes in Left Ventricular Ejection Fraction | 5 years | Left ventricular ejection fraction measured by echocardiography |
Secondary
| Measure | Time frame |
|---|---|
| Changes in Exercise Capacity | 5 years |
| Changes in Electrophysiologic Properties of Ventricular Myocardium | 6 months |
| Changes in Plasma Inflammatory Markers | 6 months |
| Changes in Left Ventricular Function | 5 years |
Countries
Slovenia
Participant flow
Recruitment details
This study consisted of an open-label randomized study design conducted at the Advanced Heart Failure and Transplantation Center at University Medical Center Ljubljana in collaboration with the Methodist DeBakey Heart Center and Stanford University.
Pre-assignment details
Patients with acute multi-organ failure or history of haematologic neoplasms were not included.
Participants by arm
| Arm | Count |
|---|---|
| SC Group 55 patients were randomized to CD34+ cell transplantation (SC group). In the SC group, peripheral CD34+cells were mobilized by G-CSF and collected via apheresis. Patients underwent myocardial scintigraphy and CD34+ cells were injected in the artery supplying the segments with reduced viability | 55 |
| Control Group 55 patients were randomized to standard medical therapy, without stem cell injection. | 55 |
| Total | 110 |
Baseline characteristics
| Characteristic | Control Group | SC Group | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 2 Participants | 5 Participants |
| Age, Categorical Between 18 and 65 years | 52 Participants | 53 Participants | 105 Participants |
| Age, Continuous | 55 years STANDARD_DEVIATION 7 | 53 years STANDARD_DEVIATION 8 | 54 years STANDARD_DEVIATION 9 |
| Region of Enrollment Slovenia | 55 participants | 55 participants | 110 participants |
| Sex: Female, Male Female | 11 Participants | 10 Participants | 21 Participants |
| Sex: Female, Male Male | 44 Participants | 45 Participants | 89 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 2 / 55 | 0 / 55 |
| serious Total, serious adverse events | 8 / 55 | 19 / 55 |
Outcome results
Primary
Changes in Left Ventricular Ejection Fraction
Left ventricular ejection fraction measured by echocardiography
Time frame: 5 years
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| SC Group | Changes in Left Ventricular Ejection Fraction | Baseline | 24.3 Percentage of ejection | Standard Deviation 6.5 |
| SC Group | Changes in Left Ventricular Ejection Fraction | 5 years | 30.0 Percentage of ejection | Standard Deviation 5.1 |
| Control Group | Changes in Left Ventricular Ejection Fraction | Baseline | 25.7 Percentage of ejection | Standard Deviation 4.1 |
| Control Group | Changes in Left Ventricular Ejection Fraction | 5 years | 23.3 Percentage of ejection | Standard Deviation 4.2 |
Primary
Heart Failure Mortality
Time frame: 5 years
Population: The minimal sample size for the study was calculated using a pre-specified power of 90% and P value of 0.05.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| SC Group | Heart Failure Mortality | 8 participants |
| Control Group | Heart Failure Mortality | 19 participants |
Comparison: The minimal sample size for the study was calculated using a pre-specified power of 90% and P value of 0.05.p-value: 0.01Log Rank
Secondary
Changes in Electrophysiologic Properties of Ventricular Myocardium
Time frame: 6 months
Secondary
Changes in Exercise Capacity
Time frame: 5 years
Secondary
Changes in Left Ventricular Function
Time frame: 5 years
Secondary
Changes in Plasma Inflammatory Markers
Time frame: 6 months