Biomedical Engineering Reference
In-Depth Information
Stem cell mobilization and cardiac repair
: Mobilizing stem cells to repair MI dam-
aged hearts—early efforts. Though stem cell mobilization occurs naturally after
injury, for unknown reasons, the response following MI is underwhelming, with
little functional impact. The goal in the RECOVER trial is to amplify this weak
response. Theoretically, one can achieve this goal either by mobilizing available
pool of patient's bone marrow stem cells, or expanding them in vitro and re-inject
them to the patient. This field is still a matter of debates and controversies as the
knowledge on the optimization of the conditions for stem cell therapy is developing
and progressing. Clinical and experimental data are difficult to synchronize due to
considerable variations in the models used in the studies, as well as the techniques
applied. Yet, the experiments with animal models moved clinicians to a series of
clinical trials. The pioneers of experimental work and their results are presented in
Table
11.2
.
Though reperfusion agents and balloon angioplasty help restore cardiac blood
flow in the critical hours following myocardial infarction, there is still often residual
tissue damage that can prevent full recovery of ventricular function. And for those
who miss this 12-h therapeutic window, the pathologic remodeling of the heart is
well under way within a week, and well established within a month.
To try and reduce, and ideally reverse, such tissue damage in the first few days or
weeks following MI, Cleveland Clinic cardiologists are now beginning to test sev-
eral stem cell-based strategies. One of these, the RECOVER trial, is a phase I clini-
cal trial that is testing whether injections of a drug, which causes a mobilization of
stem cells from the bone marrow into blood, is safe and can lead to improved LV
function following major heart attack. The other, which is still in preclinical testing,
is looking at this same mobilization drug in combination with injections of myo-
blasts that have been genetically altered to overproduce the signaling protein that
guides stem cells to damaged heart tissue. “Since restoring blood flow is not enough,
we need to explore new strategies for achieving full cardiac recovery,” says
Ellis
GS
, Director of Sones Cardiac Catheterization Laboratory at The Cleveland Clinic,
and principal investigator of the RECOVER trial. In this ongoing, double-blinded
study, patients who've had a large heart attack (LV ejection fraction less than 40%)
within the last 48 h are given subcutaneous injections of placebo or G-CSF, a mobi-
lizing agent that increases the level of circulating stem cells by a factor of 5 within
2 days. The patients are followed for 1 year, with their heart function assessed by
echocardiography at 30 days and 12 months. Previous animal studies, as well as a
European clinical trial (FIRST LINE) in which G-CSF was administered to 26
patients with MIs, showed that such mobilization can lead to modest improvement
in left ventricular function. Intra-myocardial skeletal muscle transplantation has
been demonstrated to improve cardiac function in chronic heart failure models by
regenerating muscle. Under local anesthesia, a muscle biopsy is carried out to col-
lect skeletal cells for culturing. After about 14 days, the cultured myoblasts can be
implanted into the post-MI scar during coronary artery bypass grafting of remote
myocardial areas. It is hypothesized that the transplanted autologous myoblasts will
aid in repairing the injured area and improving cardiac contractility. However, the
