Direct intramyocardial injection

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Transepicardial needle injection into the myocardium is the most straightforward and extensively studied of the delivery methods. Direct muscular injection of protein growth factors for the treatment of peripheral ischemia is well established (54-56), and direct intramyocardial delivery of these same angiogenic agents has been addressed in a number of studies demonstrating higher efficiency and preclinical efficacy (42,57-59). Direct intramyocardial injection (DIMI) may provide acute delivery efficiencies of 5-30%, depending upon the product delivered (21,60). Chronic retention has been less well documented, with suggestions of significant tissue efflux over a relatively short period of time (60) and unchanged safety concerns related to nontargeted tissue uptake. Unlike systemic or other vascular delivery, direct injection may minimize dose-dependent toxicity (e.g., VEGF- and FGF-mediated hypotension) through focal product concentration and depot tissue release (60). Most studies have not quantitatively examined delivery efficiency, but the lower than expected retention of protein products by standard injection is thought to be due to active and passive egress through the needle tract, incomplete penetration of injection needle, and interstitial pathways during each cardiac cycle (19,33).

In an attempt to enhance sustained biological effects, several unique gene transfer approaches have been combined with DIMI (18,61-73). Transepicardial injection of plasmids encoding VEGF (ph.VEGF) in murine and porcine models demonstrated dose-dependent gene expression, with peak VEGF protein levels between 1 and 5 d, and variable transgene duration from 3 d to 3 wk (61,62). Whereas some studies have reported beneficial effects related to angiogenesis and enhanced myo-cardial blood flow, others have demonstrated no clinical effects (63,64).

In a recent comparison with viral vectors (adenovirus, adeno-associ-ated virus, and herpes simplex virus), uncomplexed and complexed naked DNA proved inefficient for direct intramyocardial delivery (less than one positive cell per heart), whereas all viral vectors produced significant transgene expression up to 21 d (66). DIMI of Ad.VEGF to rat myocardium produced peak gene expression at 24-72 h that remained detectable for up to 3 wk (67). Similar transepicardial delivery of

Ad.VEGF to ischemic pigs improved regional stress perfusion and function for up to 4 wk (68). Examining myocardial protective effects, Ad.FGF injected into rabbit myocardium that was infarcted 12 d later showed evidence of angiogenesis in the pretreated areas with 50% reduction in the myocardial area at risk (69). This study broadens the potential application of angiogenic gene transfer from chronic ischemia and infarct to acute injury and even prophylactic treatment.

Delivery of adeno-associated vectors by DIMI methods has proven equally efficacious in preclinical studies, with documented myocardial transgene expression lasting for up to 8 wk (70). Also documented was improved segmental wall motion concurrent with a greater than threefold increase in total arteriolar wall area in animals treated with AAV.FGF compared to controls (71). Others have effectively delivered HJV.HGF gene product to the myocardium with resultant improvements in neovascularization, regional function, and perfusion (72,73). In these studies the effect of endogenous upregulation of HGF expression was not determined.

Successful cellular cardiomyoplasty, by DIMI and other methods, has recently undergone comprehensive review (12). These authors examined myocardial delivery of cardiomyocytes (fetal, neonatal, or adult), skeletal myoblasts, and various stem cells (embryonic stem cells, mes-enchymal or bone marrow stem cells, endothelial progenitor cells, and uncharacterized progenitor cell mixtures). No significant differences were seen in cell engraftment capabilities among various cell types, although quantitative analyses of acute and chronic transplant efficiency and cellular distribution were not independently examined. It remains unclear if cellular transplant facilitates functional improvement through differentiation into physiologically active cardiomyocyte cell types, through angiogenesis, or potentially through physical effects on remodeling with alteration in the mechanical properties of scar or ischemic tissues. The degree to which targeted delivery by transepicardial injection may affect these variables is under exploration, and this modality remains a viable investigational and treatment approach.

Because of the relative invasiveness of DIMI, clinical experience has been predictably more complex. In a phase I trial in five patients with symptomatic myocardial ischemia, naked plasma DNA encoding for VEGF was directly injected into myocardial areas of injury via mini-thoracotomy (74). Injections were safe, and at 30 and 60 d postdelivery there were significant reductions in angina, improvement in regional perfusion, and angiographic evidence of enhanced collateral flow in treated patients. In a follow-up study, 20 patients received similar treatment with improved perfusion and collateral formation again docu mented up to 60 d, and anginal improvement out to 3 mo (75). DIMI was also used to deliver Ad.VEGF to 21 coronary artery disease (CAD) patients, either concurrent with bypass surgery (n = 15) or as stand-alone therapy via mini-thoracotomy (n = 6) (76). Delivery using both methods was performed without procedurally related adverse events, demonstrating improvement in angina class and regional ventricular function at 30 d, but no significant change in perfusion or exercise performance. Direct injection of FGF in 20 patients undergoing coronary bypass surgery (in the area of left internal mammary artery [LIMA] to left anterior descending artery [LAD] anastamosis) resulted in augmented neovascularization in the anastomotic region at 1 yr (77). Skeletal myoblast transplant by DIMI methods concurrent with surgical revascularization has likewise proven safe and feasible in a small number of patients (17).

DIMI claims superiority with respect to targeted myocardial distribution. However, although a large amount of product may be introduced into focal myocardial areas, this process depends on limited epicardial visualization to identify site(s) of interest. Direct delivery is at best focal and not regional without numerous injections, and limited with respect to septal and deep myocardial access (19). Preclinical and clinical studies support the angiogenic and myogenic potential of DIMI, and this modality remains an attractive delivery option, especially as part of a hybrid procedure with mechanical revascularization.

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