The TRansendocardial Stem Cell Injection Delivery Effects on Neomyogenesis STudy (The TRIDENT Study)

Thirty (30) patients with chronic ischemic left ventricular dysfunction secondary to MI
scheduled to undergo cardiac catheterization will be enrolled in the study.This is a phase II
study intended to gain additional safety and efficacy assessments among two dose levels
previously studied in a phase I setting. In this study, a 20 million total hMSC dose and a
100 million total hMSC dose will be randomly allocated administered via the Biocardia Helical
infusion system in a blinded manner.

The technique of transplanting progenitor cells into a region of damaged myocardium, termed
cellular cardiomyoplasty, is a potentially new therapeutic modality designed to replace or
repair necrotic, scarred, or dysfunctional myocardium. Ideally, graft cells should be readily
available, easy to culture to ensure adequate quantities for transplantation, and able to
survive in host myocardium, which is often a hostile environment of limited blood supply and
immunorejection. Whether effective cellular regenerative strategies require that administered
cells differentiate into adult cardiomyocytes and couple electromechanically with the
surrounding myocardium is increasingly controversial and recent evidence suggests that this
may not be required for effective cardiac repair. Most importantly, transplantation of graft
cells should improve cardiac function and prevent adverse ventricular remodeling. To date, a
number of candidate cells have been transplanted in experimental models, including fetal and
neonatal cardiomyocytes, embryonic stem cell-derived myocytes, tissue engineered contractile
grafts9, skeletal myoblasts, several cell types derived from adult bone marrow, and cardiac
precursors residing within the heart itself. There has been substantial clinical development
in the use of whole bone marrow and skeletal myoblast preparations in studies enrolling both
post-infarction patients and patients with chronic ischemic left ventricular dysfunction and
heart failure. The effects of bone marrow-derived mesenchymal stem cells (MSCs) have also
been studied clinically.

Currently, bone marrow or bone marrow-derived cells represent a highly promising modality for
cardiac repair. The totality of evidence from trials investigating autologous whole bone
marrow infusions into patients following myocardial infarction supports the safety of this
approach. In terms of efficacy, increases in ejection fraction are reported in the majority
of the trials.

Chronic ischemic left ventricular dysfunction is a common and problematic condition;
definitive therapy in the form of heart transplantation is available to only a tiny minority
of eligible patients. Cellular cardiomyoplasty for chronic heart failure has been studied
less than for acute MI, but represents a potentially important alternative for this disease.

Inclusion Criteria:

- In order to participate in this study, a patient MUST:

1. Be ≥ 21 and < 90 years of age.

2. Provide written informed consent.

3. Have a diagnosis of chronic ischemic left ventricular dysfunction secondary to
myocardial infarction (MI) as defined by previous myocardial infarction
documented by an imaging study demonstrating coronary artery disease with
corresponding areas of akinesis, dyskinesis, or severe hypokinesis.

4. Been treated with appropriate maximal medical therapy for heart failure or
post-infarction left ventricular dysfunction. For beta-blockade, the patient must
have been on a stable dose of a clinically appropriate beta-blocker for 3 months.
For angiotensin-converting enzyme inhibition, the patient must have been on a
stable dose of a clinically appropriate agent for 1 month.

5. Be a candidate for cardiac catheterization within 5 to 10 weeks of screening as
determined by doctors.

6. Have an ejection fraction of less than or equal to 50% by gated blood pool scan,
two-dimensional echocardiogram, CT, or left ventriculogram within the prior six
months and not in the setting of a recent ischemic event.

Exclusion Criteria:

- In order to participate in this study, a patient MUST NOT:

1. Have a baseline glomerular filtration rate ≤ 35 ml/min/1.73m2.

2. Have a known, serious radiographic contrast allergy.

3. Have a Mechanical aortic valve or heart constrictive device.

4. Have a documented presence of aortic stenosis (aortic stenosis graded as 1.5cm2
or less).

5. Have a documented presence of moderate to severe aortic insufficiency
(echocardiographic assessment of aortic insufficiency graded as ≥+2).

6. Require coronary artery revascularization. Patients who require or undergo
revascularization procedures should undergo these procedures a minimum of 3
months in advance of treatment in this study. In addition, patients who develop a
need for revascularization following enrollment will be submitted for this
therapy without delay.

7. Have evidence of a life-threatening arrhythmia in the absence of a defibrillator
(non-sustained ventricular tachycardia ≥ 20 consecutive beats or complete second
or third degree heart block in the absence of a functioning pacemaker) or
Corrected for heart rate (QTc) interval > 550 ms on screening ECG

8. Automatic Implantable Cardioverter Defibrillator (AICD) firing in the past 60
days prior to enrollment.

9. Have a hematologic abnormality as evidenced by hematocrit < 25%, white blood cell
< 2,500/µl or platelet values < 100,000/µl without another explanation.

10. Have liver dysfunction, as evidenced by enzymes (AST and ALT) greater than three
times the upper limit of normal (ULN).

11. Have a coagulopathy = (INR > 1.3) not due to a reversible cause (i.e., Coumadin).
Patients on Coumadin will be withdrawn 5 days before the procedure and confirmed
to have an INR < 1.3. Patients who cannot be withdrawn from Coumadin will be
excluded from enrollment

12. Have known allergies to penicillin or streptomycin.

13. Hypersensitivity to Dimethyl Sulfoxide (DMSO).

14. Be an organ transplant recipient.

15. Have a history of organ or cell transplant rejection

16. Have a clinical history of malignancy within 5 years (i.e., patients with prior
malignancy must be disease free for 5 years), except curatively-treated basal
cell carcinoma, squamous cell carcinoma, melanoma in situ or cervical carcinoma.

17. Have a non-cardiac condition that limits lifespan to < 1 year.

18. Have a history of drug or alcohol abuse within the past 24 months.

19. Be on chronic therapy with immunosuppressant medication, such as corticosteroids
or TNFα antagonists.

20. Be serum positive for HIV, hepatitis BsAg or viremic hepatitis C.

21. Be currently participating (or participated within the previous 30 days) in an
investigational therapeutic or device trial.

22. Be a female who is pregnant, nursing, or of childbearing potential while not
practicing effective contraceptive methods. Female patients must undergo a blood
or urine pregnancy test at screening and within 36 hours prior to injection.