Peter S Macdonald FRACP,
PhD, MD. Associate Professor of Medicine,
Heart & Lung Transplant
Unit,
The prevalence of end-stage heart disease in the
Australian community is predicted to increase by 70% over the next decade (from
300,000 to 500,000). This fact, coupled with the low heart organ donation rate
and the cost and uncertain durability of mechanical hearts, provides a
compelling incentive to develop alternative therapies for patients with
end-stage heart disease. Cell transplantation to replace lost or dysfunctional
cardiac myocytes is an exciting approach that has
already progressed to clinical trials. A range of cell types has been injected
or transplanted into infarcted or myopathic
myocardium in a variety of experimental models. For example, in one rat infarct
model, intravenous injection of human-derived bone marrow stem cells within 48
hours of infarction, has been shown to induce new blood vessel formation and to
stimulate proliferation of pre-existing vasculature in and around the
myocardial infarct. The neoangiogenesis results in
decreased apoptosis of hypertrophied myocytes at the
edge of myocardial infarcts, long-term salvage of viable myocardium, reduced
collagen deposition and sustained improvement in cardiac function. Phase II
human trials suggest that intracoronary
administration of autologous bone marrow-derived stem
cells in the days following acute myocardial infarction results in reduced
infarct size and better preservation of left ventricular function at 3 months
post MI. Stem cells can be mobilised from the bone
marrow by the administration of GCSF. In a phase I trial, we are currently
administering GCSF to patients with intractable angina who are not amenable to
conventional coronary revascularisation. Preliminary
results suggest that this is safe and that it provides dramatic relief of
angina. In another approach, mesenchymal stem cells
transplanted as allografts into infarcted
segments of myocardium in rats and rabbits with heart failure,
have been shown to become incorporated within and to restore contractile
function to the infarct scar. Successful engraftment of other cell types
including smooth muscle cells and fibroblasts has also been demonstrated, but
these cell transplants are not associated with any improvement in myocardial
function. A third approach to myocardial cell replacement has been the use of autologous skeletal muscle myoblasts.
Experimental studies in the rat demonstrate that transplantation of skeletal myoblasts into infarcted
myocardium produces comparable improvements in myocardial function to that seen
with transplantation of mesenchymal stem cells.
Furthermore, the benefits of skeletal myoblast
transplantation on cardiac remodelling after experimental
myocardial infarction are additive to the benefits obtained with angiotensin-converting enzyme inhibitors. Administration of
cultured autologous skeletal myoblasts
by direct injections in and around the infarcted
myocardium during open-chest surgery results in restoration of viable
myocardial metabolism and improved myocardial contraction in patients with
heart failure. Although several hurdles remain before cell transplantation
becomes established as a treatment for heart failure, experimental and clinical
studies conducted so far have provided proof of principle and suggest that the
benefits of this approach will be additive to those provided by current drug
therapy.