Combined Bone Marrow Stem Cell Therapy and Coronary Artery Bypass Grafting for Ischemic Heart Diseases-Juniper Publishers
JUNIPER PUBLISHERS-OPEN ACCESS JOURNAL OF CARDIOLOGY & CARDIOVASCULAR THERAPY
Ischemic heart disease (IHD) is a major cause of
mortality and morbidity worldwide. It caused 1 of every 6 deaths in the
United States in 2008 [1]. It is also the major contributor to heart
failure (HF) which has become a burgeoning disease. According to
American Heart Association (AHA) projections, HF prevalence will
increase by 46% from 2012 to 2030 [2]. Patients with serious IHD
usually, have events such as myocardial infarction (MI) that can result
in irreparable loss of viable cardiac mass dramatically affecting their
cardiac functions. Despite the important advances achieved in
revascularization procedures and medical therapy, many of these patients
are left with significant disability [3]. Considering the unclear
efficacyof coronary artery bypass grafting (CABG) surgery for these
patients and the shortage of donor hearts, a rationale to develop a
novel stem cell-based regenerative therapy was provided. Numerous
studies using animal models have documented that bone marrow stem cells
(BMSC) transplantation in ischemic cardiomyopathy and acute MI is
associated with reducing infarct scar size and improving cardiac
functions [4]. These promising results of preclinical studies have led
to several clinical trials evaluating the feasibility, safety, and
efficacy of combining CABG with BMSC therapy in treating patients with
serious IHD. Since the first trial of combined CABG and BMSC
transplantation by Stamm et al. [5], several clinical trials that
followed have been able to prove both safety and feasibility of this
novel approach. However, the efficacy of this therapeutic approach
remains controversial as larger, randomized, and multicenter trials are
still needed to prove the beneficial effects of this approach [6-8].
BMSCs can be delivered to the injured myocardium via
different routes during CABG procedure. The three major
techniques used for BMSCs delivery in most studies are
- Intramyocardial injection.
- Intracoronary infusion
- Retrograde coronary sinus delivery.
These approaches are still in the stage of development and
implementation. Although the optimum delivery method has
yet to be determined, most clinical trials have reported a low
frequency of complications regardless of method of BMSCs
delivery proving the safety and feasibility of these methods.
Intramyocardial injection: This method of BMSCs delivery
is performed by direct multiple injections of cell suspensions
into target myocardial areas. The ischemic areas are identified
preoperatively using nuclear imaging and echocardiography
then visualized directly during the procedure. The prepared
BMSC suspension is injected into the border zone of the target
area after the graft-coronary anastomosis is completed [7,9].
That was the method used by Stamm et al. [5] in the first trial
of combined CABG and BMSC therapy. The injections can also
be performed at infarcted areas that will not be mechanically
revascularized during CABG due to lack of graftable coronary
vessels. This method is considered to be the most reliable and
the widest used method of BMSCs delivery during CABG [10].
However, one of its drawbacks is the risk of perforation at the
injection site. Also, cell leakage and clumping during injection
may cause nonspecific delivery and prevent uniform cell
distribution as well [11].
Intracoronary infusion: Infusing the BMSCs via coronary
arteries can be performed by injecting the cell suspensions via
the saphenous vein graft after distal anastomosis is finished, or
injecting it through distal left anterior descending artery before
completing the distal anastomosis with the internal thoracic
artery. The arteries used for the injection are determined
preoperatively by identifying the anatomical feeding vessels of
the infarcted area [12]. Unlike intramyocardial injection, this
method requires the presence of graftable coronary vessels
feeding the target area. Intracoronary infusion has been the
most practiced method of BMSCs delivery in catheter-based
studies for interventional cardiology [13].
Retrograde coronary sinus delivery: The coronary sinus
has been utilized for retrograde delivery of cardioplegic solution
in cardiac surgery. A similar technique can be used to deliver the
BMSCs via retrograde infusion through the coronary sinus to
the coronary veins [14]. Although this method has a theoretical
advantage of more homogeneous cell delivery, it is the least
investigated method of delivery [15].
In spite of the great expansion of knowledge and experience
that has been achieved in the field of regenerative medicine, a
major gap still persists in understanding the exact mechanisms
of action of cell-based therapies in cardiac regenerative
medicine. The oldest presumed mechanism was the direct cell
trans differentiation from BMSCs to contracting mature cardiac
myocytes replacing the dead ones and restoring the cardiac
functions [16]. Another theory was developed later depending
on the neovascularization capacity of the transplanted BMSCs.
Neovascularization may be beneficial in ischemic situations by
increasing blood vessel density and providing a well-developed
network of collateral vessels for maintaining adequate blood
supply to the ischemic area. However, these benefits are less
clear for old infarcted areas with no viable myocardium [17].
Later the paracrine hypothesis was developed referring to the
capacity of transplanted BMSCs to release signals and growth
factors into extracellular matrix affecting the neighboring cells
[18]. Examples of processes associated with the paracrine
effect of transplanted BMSCs may include neovascularization,
cytokine-induced myocyte growth, stimulation of endogenous
myocardial stem cells, preventing overstretch of myocytes
and maintain proper electrical behavior of myocardium by
extracellular matrix remodeling, inhibition of cardiomyocytes
hypertrophic response, and cell fusion between resident
myocytes and transplanted BMSCs [19-21].
Most of the clinical trials for combined CABG and BMSC
therapy have investigated autologous cell preparations.
Considering the advantage of avoiding immunologic rejection,
autologous sources of stem cells have been more attractive
for researchers. Nevertheless, autologous stem cell therapy is
associated with serious limitations. Especially for patients with
serious IHD who are a candidate for CABG, time is a crucial factor
that cannot be wasted on tissue harvesting, cell processing, and
quality control; which usually are not available at the same
facility where the patient will undergo his CABG surgery. In
addition, stem cell growth properties may be affected by age
as well as other comorbidities that are usually found in those
patients [22,23]. On the other hand, allogenic sources of stem
cells provide “off-the-shelf” and safe solution for those patients
being harvested from healthy young donors. Allogeneic stem cell
therapy has been proven to be safe and clinical trials combining
it with CABG have been started as well [24,25].
Stem cell therapy for IHD has been receiving a lot of
attention over the last decades. With the hope of regenerating
dead myocardium and restoring cardiac functions after ischemic
related events, researchers all over the world have passionately
investigated combined CABG with BMSC therapy. Although
both feasibility and safety were proved by several studies,controversies about efficacy still remain. Now we are in an
exciting phase of regenerative cardiac therapy. Certainly, we still
have some challenges in this field including the determining
optimal method of delivery, cell type, timing, dosage, cell survival,
and retention. In order to address these challenges first, we need
more basic science laboratory studies for a better understanding
of how this therapeutic approach may work. This will help us
improve the efficacy of current approaches and may even give
us an opportunity to develop novel approaches. Second, we need
to investigate the efficacy of current regenerative therapeutic
approaches using larger, placebo-controlled, blinded,
randomized, well designed, and multicenter clinical trials. As we
move forward in or quest for finding the optimum therapy for
IHD, we will definitely get wiser for how we can mend a broken
heart.
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