Compositions and methods for treating progressive myocardial injury due to a vascular insufficiency
The described invention provides methods and regimens for treating adverse consequences of a persistent and progressive myocardial injury-due to a vascular insufficiency that occurs early or late in a subject in need thereof, and progressive myocardial injury-preventing compositions that contain a chemotactic hematopoietic stem cell product, and, optionally, an additional active agent. The method treats ongoing vascular insufficiency affecting coronary circulation by (i) stimulating neoangiogenesis in a peri-infarct border zone, thereby improving myocardial perfusion; and, (ii) through a paracrine effect, preventing apoptosis of cardiomyocytes in the peri-infarct border zone. The neoangiogenesis and paracrine-mediated reduction of apoptosis reduces progressive myocardial cell loss, which leads to improvement in cardiac function and a reduction of risk of major adverse cardiovascular events.
1. A method of reducing progressive expansion of an area of infarcted myocardium after an acute myocardial infarction in a subject whose condition is at risk for disease progression to heart failure, comprising:
(a) first, acquiring from the subject, under sterile conditions, a population of mononuclear cells comprising CD34+ cells;
(b) second, sterilely enriching the population of mononuclear cells comprising CD34+ cells for CD34+ cells to produce enriched CD34+ cells;
(c) third, confirming that a subpopulation of potent CD34+/CXCR-4+ cells, when tested in vitro after passage through a catheter for at least 24 hours after acquiring step (a): (i) have CXCR-4 mediated chemotactic activity and move in response to SDF-1; (ii) can form hematopoietic colonies; and (iii) are at least 70% viable;
(d) fourth, formulating for delivery parenterally through a catheter a sterile pharmaceutical composition, comprising:
(i) a second portion of the enriched population produced in step (b), which contains a therapeutic amount of at least 10 million CD34+ cells comprising at least 0.5×10 6 potent CD34+/CXCR-4+ cells that have CXCR-4 mediated chemotactic activity and that move in response to SDF-1; and
(ii) a stabilizing amount of serum of at least 10% (v/v), wherein the stabilizing amount of serum is effective to retain the CXCR-4 mediated chemotactic activity and hematopoietic colony forming activity of the subpopulation of CD34+/CXCR-4+ cells in (d)(i);
(e) fifth, treating the subject by administering the sterile pharmaceutical composition to the subject parenterally on a first infusion date;
(f) sixth, repeating steps (b)-(d), in order, and optionally step (a), at a plurality of infusion dates;
wherein a therapeutic amount of the composition is effective to produce a therapeutic effect comprising a paracrine effect, a neoangiogenic effect, or a combination thereof in a peri-infarct border zone that extends beyond the area of infarcted myocardium; and
wherein the therapeutic effect is effective
to reduce progressive myocardial cell loss due to cardiomyocyte cell death in the peri-infarct border zone; to treat hypoperfusion in the peri-infarct border zone, to treat myocardial hibernation in the peri-infarct border zone, or a combination thereof, relative to controls, and
to reduce disease progression to heart failure during the subject's lifetime.
2. The method according to claim 1 , wherein acquiring step (a) is early after occurrence of the acute myocardial infarction.
3. The method according to claim 2 , wherein acquiring step (a) is after peak inflammatory cytokine cascade production in an infarcted area.
4. The method according to claim 1 , wherein acquiring step (a) is late after the acute myocardial infarction.
5. The method according to claim 4 , wherein acquiring step (a) is at least 15 days after the acute myocardial infarction.
6. The method according to claim 1 , wherein the catheter has an internal diameter of at least about 0.36 mm.
7. The method according to claim 1 , wherein administering is through the catheter into myocardium, through the catheter intravascularly, or a combination thereof.
8. The method according to claim 1 , wherein the pharmaceutical composition further includes at least one active agent that is compatible both with components (i) and (ii) of the composition.
9. The method according to claim 8 , wherein the active agent is selected from the group consisting of a cytokine, a diuretic, an anti-arrhythmic agent, a tyrosine kinase receptor agonist, an anti-anginal agent, a vasoactive agent, an anticoagulant agent, a fibrinolytic agent, and a hypercholesterolemic agent.
10. The method according to claim 9 , wherein the tyrosine kinase receptor agonist is human neuregulin 1.
11. The method according to claim 9 , wherein the cytokine is a hematopoietic stem cell mobilizing agent.
12. The method according to claim 11 , wherein the hematopoietic stem cell mobilizing agent is G-CSF, GM-CSF, or a combination thereof.
13. The method according to claim 9 , wherein the vasoactive agent is an angiotensin converting enzyme inhibitor.
14. The method according to claim 9 , wherein the antiarrhythmic agent is a beta blocker.
15. The method according to claim 1 , wherein the mononuclear cells in (a) are cellular components of a bone marrow aspirate.
16. The method according to claim 1 , wherein the mononuclear cells are cellular components of peripheral blood.
17. The method according to claim 1 , step (a) comprising apportioning the sterile mononuclear cells into a plurality of aliquots, at least one of which is frozen at −86° C., and storing the aliquots in the vapor phase of a liquid nitrogen freezer until needed.
18. The method according to claim 1 , wherein the subject is a revascularized subject.
19. The method according to claim 1 , wherein the paracrine effect comprises activation of Akt in the peri-infarct border zone.
20. The method according to claim 1 , wherein the neoangiogenic effect comprises one or more growth factors selected from the group consisting of vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), scatter factor/hepatocyte growth factor (SH/HGF), angiopoietin-1 (Ang-1), platelet derived growth factor (PDGF), transforming growth factor (TGF), and stromal derived growth factor-1 (SDF-1).
21. The method according to claim 1 , wherein the peri-infarct border zone comprises ischemic tissue and regions of normally perfused myocardium.
22. The method according to claim 1 , wherein the reduced progressive myocardial cell loss in the peri-infarct border zone reduces transition from compensated ventricular remodeling to progressive heart failure.
23. The method according to claim 1 , wherein the disease progression to heart failure includes a recurrent myocardial infarction, development of significant arrhythmias, development of acute coronary syndrome, or a combination thereof.
24. The method according to claim 23 , wherein worsening of congestive heart failure, worsening of significant arrhythmias, worsening of acute coronary syndrome, or a combination thereof would lead to premature death in the absence of treatment.