Myocardial Regeneration How Close are WE Brent

Myocardial Regeneration? How Close are WE? ? Brent Shafer PAS 646 Advisor: Dr. Hadley

Clinical Context n 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. n Pt given Aspirin, O 2, Sublingual Nitro, mophine n Labs: Elevated troponins and CK n ECG

ECG

Dx n ST elavation Myocardial Infrarction

Treatment Reperfusion Therapy n n n Thrombolytic (t-Pa) Percutaneous Revascularization (angioplasty & stenting) CABG Additional Tx: n Beta Blocker n ACE/ARB’s n DM/hypertension/hyperlipidemia/smoking cessation

So what is the problem. . n Mr. Doe part of 1. 1 Million people Dx with MI (AHA) n 25% of Men 38% of Women will die within first year of having a MI (AHA) n Since 2003: 1 out of every 2. 7 deaths in US is due to CVD (American Circulation)

New Shift in the Cardiac Paradigm n Since the 1920’s, belief was the heart was a fully differentiated organ. n Heart Possessed No Stem Cell n SO… the heart doesn’t have the ability to heal its self after an insult n Last 10 -15 years there is evidence contraindicating this belief

Goals of Presentation n Explain why there is this shift in cardiac paradigm n How might this change Tx regimen when dealing with an MI

Rat Model n 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 n They found 1 stem cell with these markers for every 1 X 104 adult myocyctes n Isolated these cells and found they possessed transcription factors and were able to differentiated into myocardial lineage n These same type of cells where found with mouse, dog, and even pig

What about us HUMANS n Eight Male Pts were given Female Heart Transplants n Then Using in situ hybridization fluorescence looked for cells in the grafted heart that had both the Y chromosome and surface markers c-kit, MDR 1, and Sca-1 on the primitive cells n 12 -16 percent of primitive cells tested positive for ckit, MDR 1, or SCa-1 also contained the Y chromosome n 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 n Using Rats: Baltrami A. et. al. Isolated Stem cells and n n n injected them in a rat, 5 hrs post MI Stem cells were labeled with a Brd. U marker Rats were sacrificed at day 10 and 20. Observed a band which was Brd. U-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 Brd. U

Another Example n Cross species engraftment of embryonic stem cells (ESC) of mouse into a sheep model n 18 sheep were used and MI induced n 2 weeks later a baseline LV ejection fraction (LVEF) taken, then ESCs given n 1 month later another LVEF n 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? ? ? n 20 patients who in the previous 5 to 9 days had an acute onset myocardial infarction n 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 n Follow was done on all 20 pts n Cell therapy had drastically reduced infarct region of 30%± 13% to 12%± 7% n 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 m. L/m 2

The Search for the Holy Grail of Tx n Hopefully, we (PAs) now know the heart is not a postmitotic organ and it does posses stem cells n Further research in the use of different types of stem cells to provide the best results for regeneration n Further research needed for best route of delivery and or the use of cytokines to induce regeneration

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