| Cardiovascular Research Laboratory
Harrison Department of Surgical Research
|Y. Joseph Woo, M.D.
Basic Science Research
|Areas of Study
V, Pirolli TJ, Bish LT, Berry MF, Burdick J, Grand T,
Woo YJ. Targeted overexpression of growth hormone by adenoviral
gene transfer preserves myocardial function and ventricular
geometry in ischemic cardiomyopathy. J Molec Cell Cardiol
MF, Pirolli TJ, Jayasankar V, Morine KJ, Moise MA, Fisher
O, Gardner TJ, Patterson PH, Woo YJ. Targeted overexpression
of leukemia inhibitory factor preserves myocardium in
postinfarction heart failure. J Thoracic and Cardiovasc
Surg 2004;128:866-875. (PDF)
Cardiovascular disease is a major global health concern.
The American Heart Association’s 2006 update reported
cardiovascular disease as the number one cause of mortality
in the USA accounting for 37% of all deaths. Nearly 7.2 million
Americans have sustained a myocardial infarction (MI). With
an increase in obesity, physical inactivity, and an aging
population, the incidence of cardiovascular disease related
morbidity and mortality is expected to increase dramatically.
An acute myocardial infarction, particularly one that is
large and transmural, can produce alterations in the topography
of both the infarcted and noninfarcted regions of the ventricle.
This adverse remodeling is influenced by three interdependent
factors: infarct size, infarct healing, and ventricular wall
stresses, and negatively impacts the function of the ventricle
and the prognosis for survival. There has been significant
interest in infarct modulation and myocardial structural preservation
to prevent these adverse outcomes. Clinical therapies include
pharmacology, percutaneous and surgical revascularization,
mechanical restraints and surgical resections which attempt
to improve myocardial efficiency and function by restoring
ventricular geometry. Unfortunately, most therapies are instituted
relatively late in the overall time course of the disease
focuses on novel, alternative strategies for the treatment
of ischemic cardiomyopathy. Strategies we have successfully
used in the past include the regulation of apoptosis, myocardial
ischemia protection, and somatotropism. We are currently exploring
three main strategies for cardiac repair: Angiogenesis, Myocardial
Regeneration, and Tissue Engineering.
Angiogenesis: In myocardial infarction, cardiomyocyte death occurs as a
result of inadequate vascular supply. One approach to limit
cell death in ischemic heart disease is to stimulate the growth
of a new microcirculation to augment tissue perfusion in the
setting of myocardial infarction.
Two angiogenic strategies we are currently exploring utilize
Endothelial Progenitor Cells (EPCs). The first approach is
to utilize the body’s endogenous machinery for angiogenesis.
When stimulated appropriately with naturally-occurring cytokines,
the production of EPCs can be significantly amplified, and
then targeted to the ischemic zone of the myocardium. The
second strategy is to harvest EPCs from the blood and/or bone
marrow, isolate, purify, and propagate the cells in vitro,
and then deliver cells to the the relatively ischemic borderzone
of a myocardial infarction.
YJ, Grand TJ, Berry MF, Atluri A, Moise MA, Hsu
V, Cohen J, Fisher O, Pirolli T, Burdick J, Taylor M,
Zentko S, Jayasankar V, Gardner TJ, Sweeney HL. Stromal
cell-derived factor and granulocyte monocyte colony stimulating
factor form a combined neovasculogenic therapy for ischemic
cardiomyopathy. J Thoracic and Cardiovasc Surg 2005;130:321-329.
images of myocardial section depicting vWF-expressing
blood vessels (green) for control
A.) Saline treated and
B.) SDF/GM-CSF treated animals.
Myocardial Regeneration: The traditional belief that the adult mammalian heart is a
terminally differentiated organ without regenerative potential
has been challenged in recent years. It is now evident that
the heart possesses the capacity for self-repair following
injury. Unfortunately, these mechanisms are inadequate to
compensate for the extensive damage which occurs in myocardial
We are actively exploring two approaches to myocardial regeneration
therapy for heart failure. Modulation of cell cycle regulation
offers an attractive approach to induce quiescent cardiomyocytes
to re-enter the cell cycle and undergo mitosis, thereby increasing
the number of functional cardiomyocytes. Cardiac Stem Cells
(CSCs) offer an alternative approach. Recently discovered
is a resident cardiac population of putative stem cells with
endothelial, smooth muscle, and striated muscle potential.
These have been referred to as Cardiac Stem Cells, and offer
a promising avenue for cardiac repair following ischemic injury.
|Woo YJ, Panlilio CM, Cheng
RK, Liao GP, Atluri P, Cohen JE, Chaudhry HW. Therapeutic
delivery of cyclin A2 induces myocardial regeneration
and enhances cardiac function in ischemic heart failure.
Circulation 2006;114:206-213. (PDF)
|Control Heart following LAD ligation
and development of ischemic heart failure. Alpha sarcomeric
actin appears red; DAPI stained nuclei appear blue. Phosphohistone
H3, a marker of mitosis, if present, would appear green.
||Cyclin A2 treated heart
showing active intranuclear mitosis. Phosphohistone H3
appears green, Alpha sarcomeric actin appears red, and
DAPI stained nuclei appear blue.
|Tissue Engineering: Tissue engineering as a method of cardiac repair is
an exciting area of research in the treatment of cardiovascular
diseases. It has translational potential in the treatment
of infarction, valvular heart disease, and end-stage heart
failure. We are currently exploring methods of creating bioengineered
sheets of beating cardiomyocytes for experimental implantation
into animal models of ischemic cardiomyopathy.