Transcript Brent Shafer

Myocardial Regeneration?
How Close are WE????
Brent Shafer
PAS 646
Advisor: Dr. Hadley
Clinical Context
 H&P: Mr. John Doe, 48 yr old WM presents
to the ED with chest pain which started 2 hrs
ago. Pn radiates down left arm. Pn is a
10/10. Pt. took sublingual nitro, partially
relieved sx’s.
 Pt given Aspirin, O2, Sublingual Nitro,
mophine
 Labs: Elevated troponins and CK
 ECG
ECG
Dx
 ST elavation Myocardial Infrarction
Treatment
Reperfusion Therapy
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Thrombolytic (t-Pa)
Percutaneous Revascularization (angioplasty &
stenting)
CABG
Additional Tx:
 Beta Blocker
 ACE/ARB’s
 DM/hypertension/hyperlipidemia/smoking cessation
So what is the problem....
 Mr. Doe part of 1.1 Million people Dx with MI
(AHA)
 25% of Men 38% of Women will die within
first year of having a MI (AHA)
 Since 2003: 1 out of every 2.7 deaths in US is
due to CVD (American Circulation)
New Shift in the Cardiac Paradigm
 Since the 1920’s, belief was the heart was a
fully differentiated organ.
 Heart Possessed No Stem Cell
 SO… the heart doesn’t have the ability to
heal its self after an insult
 Last 10-15 years there is evidence
contraindicating this belief
Goals of Presentation
 Explain why there is this shift in cardiac
paradigm
 How might this change Tx regimen when
dealing with an MI
Rat Model
 Using Confocal Microscopy looked for cells that
presented with a negative expression for the blood
lineage marker (Lin-) but were positive for stem cell
markers c-kit, Sca-1, and MDR-1
 They found 1 stem cell with these markers for every 1
X 104 adult myocyctes
 Isolated these cells and found they possessed
transcription factors and were able to differentiated
into myocardial lineage
 These same type of cells where found with mouse,
dog, and even pig
What about us HUMANS
 Eight Male Pts were given Female Heart Transplants
 Then Using in situ hybridization fluorescence looked
for cells in the grafted heart that had both the Y
chromosome and surface markers c-kit, MDR1, and
Sca-1 on the primitive cells
 12-16 percent of primitive cells tested positive for ckit, MDR1, or SCa-1 also contained the Y
chromosome
 The transplanted heart contained myocytes with the
Y chromosome in 9±4 percent, as well as, arterioles
10±3 percent, and capillaries 7±1
How can we use the Stem Cells
 Using Rats: Baltrami A. et. al. Isolated Stem cells and
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injected them in a rat, 5 hrs post MI
Stem cells were labeled with a BrdU marker
Rats were sacrificed at day 10 and 20.
Observed a band which was BrdU-labeled indicating
regenerating myocardium in 9 of 12 rats at day 10,
and 10 of 10 rats at day 20
A reduction of infarct size from 53% ± 7% to 40% ±
5% at day 10 group and 70% ± 9% to 48% ± 7% in
day 20 group
The regenerated myocardium constituted of small
myocytes, capillaries, and arterioles all positively
labeled with BrdU
Another Example
 Cross species engraftment of embryonic stem
cells (ESC) of mouse into a sheep model
 18 sheep were used and MI induced
 2 weeks later a baseline LV ejection fraction
(LVEF) taken, then ESCs given
 1 month later another LVEF
 Control deteriorated from the baseline by a
median of 9.9%, treated group had a median
increase of 6.6%
Are there any Clinical Trials???
 20 patients who in the previous 5 to 9 days
had an acute onset myocardial infarction
 Ten of these patients were then treated with
a percutaneous transluminal coronary
angioplasty (PTCA), where the balloon
catheter was inserted into the infracted area
of the heart and injected 6 or 7 infusion of
mononuclear cells (each infusion containing
1.5 to 4 X 106 cells), other received PTCA
and other standard of care treatment
Results
 Follow was done on all 20 pts
 Cell therapy had drastically reduced infarct
region of 30%±13% to 12%±7%
 Both groups had non-significant increases in
ejection fraction, but cell therapy did
decrease the perfusion defect by 26%, while
increasing the stroke volume index from 49±7
to 56±7 mL/m2
The Search for the Holy Grail of Tx
 Hopefully, we (PAs) now know the heart is not
a postmitotic organ and it does posses stem
cells
 Further research in the use of different types
of stem cells to provide the best results for
regeneration
 Further research needed for best route of
delivery and or the use of cytokines to induce
regeneration
References
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