Ariana G. Ojalvo*
Nelson S. Vispo
Juan F. Batista
Jose F. Montequin
Jose L. Reyes
Financial support: This work has been supported by the Center for Genetic Engineering and Biotechnology, Havana, Cuba.
Coronary heart disease is a major cause of mortality and morbidity in humans. Although present treatments are often helpful, restenosis of coronary vessels occurs in 30-35% of the patients. On the other hand, there is a significant group of patients which angioplasty or bypass may not be feasible because of poor target vessels, lack of conduits, or unacceptable operative risk. Despite maximal pharmacological therapy, many of these patients remain incapacitated by frequent anginal attacks. Therefore, alternative treatments are needed.
Therapeutic angiogenesis is a novel concept consisting in the use of angiogenic growth factors to expedite and/or augment collateral artery development in ischemic tissues. Vascular endothelial growth factor (VEGF), an endothelial cell-specific mitogen, has been shown to promote therapeutic angiogenesis in animal models of hindlimb and myocardial ischemia.
Adenovirus-mediated gene transfer of the 121-amino acid isoform of VEGF (VEGF121) have also been successfully delivered to ischemic myocardium of animals and patients. However, virus administration can lead to immune responses that could cause serious immunopathology. The use of naked plasmid DNA obviates these immunological concerns and simplifies the transfection protocol. In the present study, we hypothesized that intramyocardial administration of naked plasmid DNA encoding VEGF121 could improve myocardial perfusion and function in a porcine model of myocardial ischemia.
Nine healthy swine, having normal perfusion/function patterns, underwent surgical induction of myocardial ischemia. Three weeks later, myocardial perfusion and function were assessed by SPECT imaging. Light or moderate ischemic areas were localized in all animals.
Animals were treated with pVEGF121 or saline by intramyocardial injection through a second thoracotomy. Four weeks after treatment, most of pVEGF121-treated animals evolved to a normal perfusion. In contrast, all control animals exhibited similar or impaired ischemic conditions. In pVEGF121 group, an important reduction in the ischemic area was typically observed 4 weeks after gene transfer (week 9) when compared with baseline (week 4). In contrast, control SPECT images showed persistent perfusion defects at week 9.
Before gene transfer (week 4), mean values of 99mTc-MIBI uptake index were similar in both groups (pVEGF121 = 54.7 ± 6.6%, control = 53.7 ± 7.4%; P = NS) and lower than basal 99mTc-MIBI uptake index (> 80% in both groups). However, at week 9, pVEGF121-treated animals exhibited significantly higher 99mTc-MIBI uptake index compared with the control group (pVEGF121 = 71.9 ± 6.8% versus control = 53.2 ± 11.5%, P<0.05). These results provide evidence about a 35 % improvement in myocardial function. No side effects could be associated to the administration of pVEGF121 plasmid.
The present study demonstrates that intramyocardial injection of pVEGF121 plasmid DNA results in sufficient VEGF121 expression to significantly improve myocardial perfusion and function in a porcine model of myocardial ischemia. Such a strategy may be feasible in patients with ischemic heart disease who are not candidate to conventional revascularization procedures.
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