A strategy of retrograde injection of bone marrow mononuclear cells into the myocardium for the treatment of ischemic heart disease.
OBJECTIVE
Bone marrow cells implantation (BMI) has been reported to efficiently improve ischemic heart disease. However, BMI strategies are generally invasive. To establish a BMI strategy for ischemic heart disease, we performed implantation of autologous cryopreserved mononuclear cells (MNCs) from bone marrow (BM) retrogradely into the myocardium via the coronary vein in pigs with acute myocardial infarction (AMI) and old myocardial infarction (OMI).


METHODS
BM cells were harvested from the pigs' fumurs. MNCs were collected by centrifugation and were cryopreserved. Anterior myocardial infarction was induced by occlusion of the midportion of the left anterior descending coronary artery without surgical intervention. Frozen BM cells were quickly thawed and injected retrogradely via the coronary vein into the myocardium through a single balloon infusion catheter 6 h and 2 weeks after the induction of infarction. Four weeks after implantation, coronary arteriograms were obtained, cardiac function was analyzed with the use of a conductance catheter, and histopathologic analysis was performed with a confocal laser microscope. Plasma levels of natriuretic peptides and angiogenic growth factors were measured after BMI.


RESULTS
Flow cytometric analysis revealed that 90% of cryopreserved BM cells were viable in vitro. Labeled BM cells were entirely distributed around in the infarcted area of maycardium in pigs. BMI increased collateral neovascuralization in infarcted hearts. BMI significantly improved cardiac function in AMI with BMI and OMI with BMI groups. BMI also increased the formation of microcapillary arteries in infarcted hearts. Levels of natriuretic peptides were significantly decreased, and levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (FGF2) were significantly increased after BMI. Confocal laser microscopy revealed the presence of proliferative and activated myocardial cells in infarcted hearts after BMI.


CONCLUSIONS
The retrograde infusion of cryopreserved BM cells into myocardium efficiently induced angiogenesis and improved cardiac function in pigs with AMI or OMI. These results suggest that the present strategy of BMI will be safe and feasible as an angiogenic cell therapy for ischemic heart disease.
Yokoyama
Shin-Ichiro
S
Department of Medicine, Nihon University School of Medicine, 30-1, Ooyaguchi-kamimachi, Itabas, Tokyo 173-8610, Japan.
Fukuda
Noboru
N
Li
Yuxin
Y
Hagikura
Kazuhiro
K
Takayama
Tadateru
T
Kunimoto
Satoshi
S
Honye
Junko
J
Saito
Satoshi
S
Wada
Mika
M
Satomi
Aya
A
Kato
Maiko
M
Mugishima
Hideo
H
Kusumi
Yoshiaki
Y
Mitsumata
Masako
M
Murohara
Toyoaki
T
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000097:blood; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology*; D016026:Bone Marrow Transplantation / Q000379:methods*; D003331:Coronary Vessels / Q000502:physiology; D015925:Cryopreservation; D016222:Fibroblast Growth Factor 2 / Q000097:blood; D007267:Injections; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology / Q000628:therapy; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D009206:Myocardium / Q000166:cytology / Q000473:pathology; D020097:Natriuretic Peptide, Brain / Q000097:blood; D018919:Neovascularization, Physiologic; D013552:Swine; D042461:Vascular Endothelial Growth Factor A / Q000097:blood
D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2; D020097:Natriuretic Peptide, Brain; D009320:Atrial Natriuretic Factor