Treatment of reperfused ischemia with adipose-derived stem cells in a preclinical Swine model of myocardial infarction.

The aim of the study was to determine the long-term effect of transplantation of adipose-derived stromal cells (ADSCs) in a preclinical model of ischemia/reperfusion (I/R). I/R was induced in 28 Goettingen minipigs by 120 min of coronary artery occlusion followed by reperfusion. Nine days later, surviving animals were allocated to receive transendocardial injection of a mean of 213.6 ± 41.78 million green fluorescent protein (GFP)-expressing ADSCs (n = 7) or culture medium as control (n = 9). Heart function, cell engraftment, and histological analysis were performed 3 months after transplantation. Transplantation of ADSCs induced a statistically significant long-lasting (3 months) improvement in cardiac function and geometry in comparison with control animals. Functional improvement was associated with an increase in angiogenesis and vasculogenesis and a positive effect on heart remodeling with a decrease in fibrosis and cardiac hypertrophy in animals treated with ADSCs. Despite the lack of cell engraftment after 3 months, ADSC transplantation induced changes in the ratio between MMP/TIMP. Our results indicate that transplantation of ADSCs, despite the lack of long-term significant cell engraftment, increases vessel density and prevents adverse remodeling in a clinically relevant model of myocardial infarction, strongly suggesting a paracrine-mediated effect. ADSCs thus constitute an attractive candidate for the treatment of myocardial infarction.

Repeated implantation of skeletal myoblast in a swine model of chronic myocardial infarction.

AIMS: Although transplantation of skeletal myoblast (SkM) in models of chronic myocardial infarction (MI) induces an improvement in cardiac function, the limited engraftment remains a major limitation. We analyse in a pre-clinical model whether the sequential transplantation of autologous SkM by percutaneous delivery was associated with increased cell engraftment and functional benefit. METHODS AND RESULTS: Chronically infarcted Goettingen minipigs (n = 20) were divided in four groups that received either media control or one, two, or three doses of SkM (mean of 329.6 x 10(6) cells per dose) at intervals of 6 weeks and were followed for a total of 7 months. At the time of sacrifice, cardiac function was significantly better in animals treated with SkM in comparison with the control group. A significantly greater increase in the DeltaLVEF was detected in animals that received three doses vs. a single dose of SkM. A correlation between the total number of transplanted cells and the improvement in LVEF and DeltaLVEF was found (P < 0.05). Skeletal myoblast transplant was associated with an increase in tissue vasculogenesis and decreased fibrosis (collagen vascular fraction) and these effects were greater in animals receiving three doses of cells. CONCLUSION: Repeated injection of SkM in a model of chronic MI is feasible and safe and induces a significant improvement in cardiac function.

A comparison between percutaneous and surgical transplantation of autologous skeletal myoblasts in a swine model of chronic myocardial infarction.

OBJECTIVE: Our aim was to compare the efficacy of surgical versus percutaneous administration of skeletal myoblasts (SkM) in a swine model of chronic myocardial infarction and to determine the mechanism(s) involved in their beneficial effect. METHODS: Two months after induction of myocardial infarction (MI), Goettingen miniature pigs underwent autologous SkM transplant either by direct surgical injection (n=6) or percutaneous access and intramyocardial delivery under fluoroscopic and echocardiographic guidance (n=6). Control animals received media alone (n=4). Functional analysis was performed by 2D echocardiography. Myoblast engraftment, in vivo cell differentiation, vessel formation, fibrosis, and the ratio between collagen type I/III deposition were analyzed in the infarct (IA) and non-infarct area (NIA) by immunohistochemistry. RESULTS: Animals received a median of 407.55+/-115x10(6) BrdU-labeled autologous SkM. Myoblast transplant was associated with a statistically significant increase in left ventricular ejection fraction (p<0.01), increased vasculogenesis and decreased fibrosis (p<0.05), and reduced collagen type I/III ratio in the IA and NIA areas as compared with control animals. No differences were found between groups receiving SkM by percutaneous or surgical access. CONCLUSIONS: Our results indicate that increased vasculogenesis and changes in matrix remodeling with decreased fibrosis are associated with the beneficial effect of SkM transplant in chronic MI. The equivalent benefit observed from surgical and percutaneous delivery has important clinical implications.

Dietary supplementation with vitamins C and E prevents downregulation of endothelial NOS expression in hypercholesterolemia in vivo and in vitro.

Impaired endothelium-dependent vasodilation has been associated with decreased NO bioavailability in hypercholesterolemia. This study aimed to determine whether antioxidant vitamins C and E could improve hypercholesterolemia-derived endothelial dysfunction in the porcine model, and whether observed in vivo results could be reproduced in vitro by incubation of coronary endothelial cells (EC) in the presence of native low-density lipoproteins (LDL). Adult mini-pigs were fed standard (C), cholesterol rich (HC) or cholesterol rich diet supplemented with vitamins C and E (HCV). Endothelium-dependent blood flow increase in response to acetylcholine was determined. Endothelial nitric oxide synthase (eNOS) expression was measured in arterial samples and in EC incubated with LDL isolated from porcine plasma. Vasomotor response to acetylcholine in HC was significantly lower (P<0.05) than control and HCV. There was a significant (P<0.05) decrease in eNOS immunoreactivity in HC, compared with HCV and control. Native LDL from HC, but not from HCV, induced a significant decrease in eNOS expression. Vitamins C and E treatment improved the endothelium-dependent vasomotor capacity and prevented decreased expression of eNOS in hypercholesterolemic pigs. A similar effect could be demonstrated in vitro, by incubation of EC with native LDL, suggesting that the effect of physiologically-modified LDL on eNOS could have a role in recovering vascular function.