Background-The noninvasive, tissue-specific delivery of therapeutic agents to the heart would be a valuable clinical tool.This study addressed the hypothesis that albumin-coated microbubbles could be used to effectively deliver an adenoviral transgene to rat myocardium by ultrasound-mediated microbubble destruction. Methods and Results-Recombinant adenovirus containing ␤-galactosidase and driven by a constitutive promoter was attached to the surface of albumin-coated, perfluoropropane-filled microbubbles. These bubbles were infused into the jugular vein of rats with or without simultaneous echocardiography. Additional controls included ultrasound of microbubbles that did not contain virus, virus alone, and virus plus ultrasound. One group underwent ultrasoundmediated destruction of microbubbles followed by adenovirus infusion. Rats were killed after 4 days and examined for ␤-galactosidase expression. The hearts of all rats that underwent ultrasound-mediated destruction of microbubbles containing virus showed nuclear staining with 5-bromo-4-chloro-3-indolyl-␤-D-galactopyranoside substrate, indicating expression of the transgene. None of the control animals showed myocardial expression of the ␤-galactosidase transgene. By quantitative analysis, ␤-galactosidase activity was 10-fold higher in the treated group than in controls (PϽ0.0001). Conclusions-Ultrasound-mediated destruction of albumin-coated microbubbles is a promising method for the delivery of bioactive agents to the heart.

Adenovirus-mediated transfer of COX-1 to angioplasty-injured carotid arteries was efficacious in augmenting PGI2 synthesis and was associated with an inhibition of thrombosis when a relatively high titer of adenovirus was instilled.

No abstract

Cholesterol acquired by extrahepatic tissues (from de novo synthesis or lipoproteins) is returned to the liver for excretion in a process called reverse cholesterol transport (RCT). We undertook studies to determine if RCT could be enhanced by up-regulating individual steps in the RCT pathway. Overexpression of 7␣-hydroxylase, Scavenger receptor B1, lecithin:cholesterol acyltransferase (LCAT), or apoA-I in the liver did not stimulate cholesterol efflux from any extrahepatic tissue. In contrast, infusion of apoA-I⅐phospholipid complexes (rHDL) that resemble nascent HDL markedly stimulated cholesterol efflux from tissues into plasma. Cholesterol effluxed to rHDL was initially unesterified but by 24 h this cholesterol was largely esterified and had shifted to normal HDL (in mice lacking cholesteryl ester transfer protein) or to apoB containing lipoproteins (in cholesteryl ester transfer protein transgenic mice). Most of the cholesterol effluxed into plasma in response to rHDL came from the liver. However, an even greater proportion of effluxed cholesterol was cleared by the liver resulting in a transient increase in liver cholesterol concentrations. Fecal sterol excretion was not increased by rHDL. Thus, although rHDL stimulated cholesterol efflux from most tissues and increased net cholesterol movement from extrahepatic tissues to the liver, cholesterol flux through the entire RCT pathway was not increased.Cholesterol that has been acquired by extrahepatic tissues (from de novo synthesis or lipoproteins) is returned to the liver for excretion in a process called reverse cholesterol transport (RCT) 1 (1-3). The first step in the RCT pathway is efflux of cholesterol from cell membranes to nascent HDL in interstitial fluid (2, 3). Nascent HDL are discoidal pre-␤-migrating complexes of phospholipid and apoA-I (other amphipathic apoproteins such as apoE and apoA-IV may also be present). These particles are secreted by the liver (4, 5) and small intestine (6) and are also formed during the metabolism of triglyceride-rich lipoproteins from excess surface material. In addition, lipid-free apoA-I can mediate the efflux of cholesterol and phospholipid from cells generating pre␤-migrating nascent HDL (7,8). ATP-binding cassette transporter 1 (ABCA1) appears to play a key role in this process although the exact mechanism is unclear (9 -12). Cholesterol that is transferred to nascent HDL is esterified by lecithin: cholesterol acyltransferase (LCAT) to cholesteryl esters, which by virtue of their hydrophobicity move into the core of the HDL particle resulting in the formation of ␣-migrating spherical HDL. HDL cholesteryl esters are cleared from plasma mainly by the liver (13-16). HDL cholesteryl ester uptake by the liver is mediated by the scavenger receptor BI (SR-BI), which selectively transports HDL cholesteryl esters resulting in an HDL particle of reduced size and cholesteryl ester content (17, 18). In species with cholesteryl ester transfer protein, a portion of HDL cholesteryl ester is transferred to lower density apoB-c...

A bioresorbable, expandable poly(L-lactic acid) stent has been designed, based on a linear, continuous coil array principle, by which multiple furled lobes convert to a single lobe upon balloon expansion, without heating. Stent strength and compliance are sufficient to permit deployment by a conventional balloon angioplasty catheter. Several multiple lobe configurations were investigated, with expansion ratios ranging from 1.4 to 1.9 and expanded diameters ranging from 2.3 to 4.7 mm. Compression resistance of the expanded stent is dependent on fiber coil density and fiber ply. A range sufficient for endovascular service was obtained, with less than 4% elastic recoil in six day saline incubation studies. Surface plasma treatment with di(ethylene glycol) vinyl ether significantly reduced platelet adhesion in a 1 h porcine arteriovenous shunt model. Patency was maintained in one week implant studies in the porcine common femoral artery. However, a strong inflammatory response, and significant reduction of the vascular lumen were observed following two weeks implantation. The design principles and fabrication techniques for this bioresorbable stent are sufficiently versatile that a broad range of applications can be addressed. Much work remains to be done, including long-term evaluation of the inflammatory response, and of polymer degradation. The results of this study demonstrate the feasibility of expandable biodegradable stent design and deployment by conventional means.