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J Thorac Cardiovasc Surg 2003;125:441-442
© 2003 The American Association for Thoracic Surgery

Letters to the Editor

Angiogenesis by means of endothelial cell transplantation

Milwaukee Heart Institute, Aurora/Sinai Medical Center, Milwaukee, Wis^a, Lenox Hill Heart & Vascular Institute, Cardiovascular Research Foundation, Lenox Hill Hospital, New York, NY^b

To the Editor:

In their article, "Angiogenesis by Endothelial Cell Transplantation," Kim and associates ¹ present results of a novel and intriguing approach to angiogenic therapy. Their preliminary report that endothelial cell transplantation into a myocardial scar accelerates angiogenesis suggests a promising alternative to angiogenic gene or protein therapy. About the same time that their article was published, we ² presented similar results before the American Heart Association at our annual scientific session (Anaheim, Calif) in November 2001.

Interestingly, we created our model of ischemic cardiomyopathy by placing an ameroid constrictor on the branch of the circumflex artery in 12 adult sheep.

In our experiment, 4 weeks after constriction, we randomly assigned 3 groups (4 animals per group) to transpericardial injection (3 sites per animal): sham treatment (saline solution with denatured cells), control (no injections), and endothelial cell fibrin meshwork groups (autologous mature endothelial cells, 5 x 10⁵ per injection site harvested from jugular veins). Eight weeks after transepicardial treatment, animals were assessed for myocardial function (by means of echocardiography), myocardial blood flow (MBF), and capillary area (by means of histology).

We demonstrated improved capillary density and MBF in keeping with their speculation that, "A coronary ligation model of myocardial infarction, in which a more extensive peri-infarct border zone could harbor viable but hypoperfused cardiomyocytes and endothelial cells, might result in greater angiogenesis."

One month after constriction, MBF in the ischemic myocardium decreased to 70% of baseline value (P < .001). Two months after reoperation and the beginning of treatment, animals were killed, and MBF was found to have decreased to 28% versus baseline values in the control and saline solution groups (P < .001). MBF in the endothelial cell group significantly increased to 108%.

In normal nonischemic myocardium in all 3 groups, there were 205.54 ± 12.31 capillaries/mm². Three months after constriction (and 2 months after reoperation and beginning of treatment) in the control and saline solution groups, there was a decrease up to 51% in capillaries per square millimeter (P < .001 vs baseline). However, although this decreased significantly in the control and saline solution groups versus baseline values, in the endothelial cell group this increased to 146% (P < .001). Hence all of our results confirmed those in the report of Kim and associates. ¹

However, they also concluded that "increasing blood flow by endothelial cell transplantation in this model did not improve contractility or prevent ventricular dilatation," and "we plan to perform autologous endothelial cell transplantation in our clinically relevant porcine model of occlusion of the left anterior descending coronary artery. We anticipate that angiogenesis may improve regional and global function."

In our investigation, 4 weeks after constriction, left ventricular ejection fraction (LVEF) decreased to 75% (P < .001). Two months later, LVEF decreased to 57% in the control and saline groups (P < .001 vs 4 weeks and baseline). In the endothelial cell group LVEF increased to 89% of baseline values but continued to be less than baseline value (P < .05). However, LVEF in this group was significantly better than in the control and saline solution groups (P < .001).

On the basis of our data, we think that use of endothelial cell transplantation within a 3-dimensional matrix system can be used to induce angiogenesis in patients who cannot be adequately revascularized by using standard techniques. Exploring autologous mature endothelial cell transplantation might become a useful alternative to gene and protein therapy. We recently completed studies involving a large number of animals; these results are pending.

References

1. Kim E-J, Li R-K, Weisel RD, Mickle DA, Jia ZQ, Tomita S, et al. Angiogenesis by endothelial cell transplantation. J Thorac Cardiovasc Surg. 2001;122:963_71.[Medline]
   
2. Chekanov V, Nikolaychik V, Tchekanov G, Dangas G, Roubin G, Leon M, et al. Transplantation of autologous endothelial cells in a fibrin meshwork induces angiogenesis and improves myocardial function in an animal model of ischemic cardiomyopathy [abstract]. Circulation. 2001;104(suppl 17):II260.
   

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