Combined transmyocardial revascularization and cell-based angiogenic gene therapy increases transplanted cell survival.
We hypothesized that pretreatment of an infarcted heart by mechanical transmyocardial revascularization (TMR) before transplantation of bone marrow cells (BMCs) or BMC-expressing angiogenic growth factors would increase transplanted BMC survival and enhance myocardial repair. Female Lewis rats underwent coronary ligation 3 wk before creation of 10 needle TMR channels (3 groups) or no TMR (3 groups), followed by transplantation of 3 x 10(6) male donor BMCs, BMC transfected with vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and insulin-like growth factor-1 (IGF-1) (BMC + VBI), or medium alone. At 1, 3, and 7 days, we evaluated transplanted cell survival, vascular densities, and left ventricular (LV) function (N = 4 per group x 6 groups x 3 time points). At 3 days, vascular densities in the scar were increased by TMR + BMC + VBI and by BMC + VBI (P < 0.05), and at 7 days, vascular densities were greatest in rats receiving TMR + BMC + VBI (P < 0.05). Transplanted cell survival at 3 and 7 days was increased by TMR and by BMC + VBI. Combined therapy with TMR + BMC + VBI resulted in the greatest cell survival at 3 days (P < 0.05) versus BMC. After 7 days, LV ejection fraction (LVEF) was lowest in rats receiving neither BMC nor TMR and greatest in rats receiving TMR + BMC + VBI (P = 0.004). We concluded that mechanical pretreatment of infarcted myocardium by TMR enhances the effect of subsequent cell-based gene therapy on transplanted cell survival, angiogenesis, and LV function. Scar pretreatment with TMR combined with cell-based multigene therapy may maximize myocardial repair.
Spiegelstein
Dan
D
Division of Cardiovascular Surgery, Toronto General Hospital, University Health Network, 200 Elizabeth Street, Toronto, Ontario, Canada.
Kim
Christopher
C
Zhang
Yaoguang
Y
Li
Guangming
G
Weisel
Richard D
RD
Li
Ren-Ke
RK
Yau
Terrence M
TM
D042501:Angiogenic Proteins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism*; D016026:Bone Marrow Transplantation; D002470:Cell Survival; D002478:Cells, Cultured; D003131:Combined Modality Therapy; D003331:Coronary Vessels / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D004195:Disease Models, Animal; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D015316:Genetic Therapy / Q000379:methods*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008026:Ligation; D008297:Male; D009203:Myocardial Infarction / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology / Q000601:surgery / Q000628:therapy*; D009204:Myocardial Revascularization / Q000379:methods*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology; D018919:Neovascularization, Physiologic; D051381:Rats; D011917:Rats, Inbred Lew; D013314:Stress, Mechanical; D013318:Stroke Volume; D013997:Time Factors; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D016277:Ventricular Function, Left