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Pleiotrophin (PTN) is a growth factor with both pro-angiogenic and limited pro-tumorigenic activity. We evaluated the potential for PTN to be used for safe angiogenic gene therapy using the full length gene and a truncated gene variant lacking the domain implicated in tumorigenesis. Mouse myoblasts were transduced to express full length or truncated PTN (PTN or T-PTN), along with a LacZ reporter gene, and injected into mouse limb muscle and myocardium. In cultured myoblasts, PTN was expressed and secreted via the Golgi apparatus, but T-PTN was not properly secreted. Nonetheless, no evidence of uncontrolled growth was observed in cells expressing either form of PTN. PTN gene delivery to myocardium, and non-ischemic skeletal muscle, did not result in a detectable change in vascularity or function. In ischemic hindlimb at 14 days post-implantation, intramuscular injection with PTN-expressing myoblasts led to a significant increase in skin perfusion and muscle arteriole density. We conclude that (1) delivery of the full length PTN gene to muscle can be accomplished without tumorigenesis, (2) the truncated PTN gene may be difficult to use in a gene therapy context due to inefficient secretion, (3) PTN gene delivery leads to functional benefit in the mouse acute ischemic hindlimb model.

Objective: Myocardial regeneration based on stem cell transplantation has emerged as a potential therapeutic approach toward replacing myocardial scar with functioning contractile tissue after myocardial infarction (MI). Considerable interest has focused on bone marrow cells (BMCs) and endothelial progenitor cells (EPCs) because they appear successful in attenuating remodeling following acute MI. However, preclinical experiments toward this goal have been limited to treatment within hours of an MI, in contrast to human trials, in which cell treatment has been performed several days later after patient stabilization and autologous cell harvesting. We sought to compare the therapeutic effects of different types of putative stem and progenitor cells in a mouse model of MI using a novel closed-chest echo-guided injection approach to deliver cells 3 days after infarction.Methods: MI was surgically induced in adult male mice by performing a mid-LAD ligation. Closed-chest echo-guided injection of cells (5 x 105 in 5 ul or saline control (HBSS) into myocardium at the peri-infarct border zone was performed at day 3 post-MI in the following groups (n=8/group): mouse BMCs (mBMCs) into C57BL/6 mice, human BMCs into immunodeficient SCID mice, mBMCs into SCID, human EPCs into SCID, and HBSS into both C57BL/6 and SCID as controls. Echocardiography was accomplished in a blinded manner with a Vevo 660 system (VisualSonics, Toronto) at baseline, 2 days post-MI (before injection), and at day 28 post-MI.Results: Left ventricular ejection fraction (LVEF) was uniformly reduced from 57.2+/-4.0% to 38.4+/-3.7% (p<0.0001) after MI in all groups. Mice injected with mBMCs showed the best effect with significant improvement in global LVEF (37.8+/-2.3% vs 44.4+/-6.3%, p=0.03), and in regional wall motion index in the infarct area (1.79+/-0.21 vs 1.4+/-0.29, p=0.02) at day 28, and there was a tendency toward less dilation of cardiac dimensions compared with that before injection. The global systolic function of the treatment group injected with mBMCs was significantly better preserved than that of its corresponding control group (44.4+/-6.3% vs 31.1+/-10.4%, p<0.0005). Human EPC injection showed a non-significant trend toward improvement of LVEF and less LV dilation, while the LVEF of its corresponding control group continued to decrease, resulting in a significant difference between the EPC group and its controls at day 28 (41.5 +/-4.3 vs 32.1+/-6.3, p<0.0005).Conclusions: Unfractionated mouse bone marrow cells attenuated ventricular remodeling and partially preserved LV function when delivered several days after surgically-induced MI. However, injection of different cell types affects LV function to varying extents. The percutaneous echo-guided injection approach made it possible to assess therapeutic cell implantation at a clinically relevant time after MI in a mouse model.Molecular Therapy (2006) 13, S175–S175; doi: 10.1016/j.ymthe.2006.08.521 [ABSTRACT FROM AUTHOR]

Background: In observational studies of patients undergoing percutaneous coronary intervention (PCI), surgical ineligibility is associated with increased mortality. Whether the use of hemodynamic support during PCI can mitigate the adverse prognostic importance of surgical ineligibility is unknown., Methods and Results: We sought to evaluate the association between request for surgical consultation (presumed surgical ineligibility) prior to PCI and clinical outcomes in 427 patients with multivessel coronary artery disease or unprotected left main disease and severely reduced left ventricular systolic function undergoing PCI assisted by hemodynamic support (intraaortic balloon pump or Impella) from the PROTECT II randomized trial. Patients in whom surgical consultation was requested prior to PCI (n = 201) were compared with those in whom surgical consultation was not requested (n = 226). The primary endpoint of this analysis was the composite of 90-day major adverse cardiac and cerebrovascular events (MACCE). Demographic and procedural variables were similar between patients receiving surgical consultation and patients not receiving surgical consultation, with the exception that the prevalence of prior coronary artery bypass graft surgery was significantly higher in patients not receiving surgical consultation (42.0% vs 25.4%; P<.001); these patients also had a higher proportion of lesions within a saphenous vein graft, and a greater prevalence of moderate/severe vessel calcification. MACCE rate at 90 days was similar in patients receiving surgical consultation compared with patients not receiving surgical consultation (23.4% vs 29.0%, respectively; P=.19)., Conclusions: In this high-risk cohort of patients undergoing hemodynamically supported PCI, clinical outcome was not associated with an antecedent request for surgical consultation (presumed surgical ineligibility). Whether the use of hemodynamically supported PCI can lessen the risk conferred by surgical ineligibility requires further study.