David S Wang

Stanford Medicine, Stanford, California, United States

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Publications (17)86.06 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: The efficacy and safety of cardiac gene therapy depend critically on the level and the distribution of therapeutic gene expression following vector administration. We aimed to develop a titratable two-step transcriptional amplification (tTSTA) vector strategy, which allows modulation of transcriptionally targeted gene expression in the myocardium. We constructed a tTSTA plasmid vector (pcTnT-tTSTA-fluc), which uses the cardiac troponin T (cTnT) promoter to drive the expression of the recombinant transcriptional activator GAL4-mER(LBD)-VP2, whose ability to transactivate the downstream firefly luciferase reporter gene (fluc) depends on the binding of its mutant estrogen receptor (ERG521T) ligand binding domain (LBD) to an ER ligand such as raloxifene. Mice underwent either intramyocardial or hydrodynamic tail vein (HTV) injection of pcTnT-tTSTA-fluc, followed by differential modulation of fluc expression with varying doses of intraperitoneal raloxifene prior to bioluminescence imaging to assess the kinetics of myocardial or hepatic fluc expression. Intramyocardial injection of pcTnT-tTSTA-fluc followed by titration with intraperitoneal raloxifene led to up to tenfold induction of myocardial fluc expression. HTV injection of pcTnT-tTSTA-fluc led to negligible long-term hepatic fluc expression, regardless of the raloxifene dose given. The tTSTA vector strategy can effectively modulate transgene expression in a tissue-specific manner. Further refinement of this strategy should help maximize the benefit-to-risk ratio of cardiac gene therapy.
    Molecular imaging and biology: MIB: the official publication of the Academy of Molecular Imaging 08/2013; 16(2). DOI:10.1007/s11307-013-0673-4 · 2.77 Impact Factor
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    ABSTRACT: Hypoxia-inducible factor-1 alpha (HIF-1α) gene therapy holds great promise for the treatment of myocardial ischemia. Both pre-clinical and clinical evaluations of this therapy are underway, and can benefit from a vector strategy that allows noninvasive assessment of HIF-1α expression as an objective measure of gene delivery. We have developed a novel bi-directional plasmid vector (pcTnT-HIF-1α-VP2-TSTA-fluc), which employs the cardiac troponin T (cTnT) promoter in conjunction with a two-step transcriptional amplification (TSTA) system to drive the linked expression of a recombinant HIF-1α gene (HIF-1α-VP2) and the firefly luciferase gene (fluc). The firefly luciferase (FLuc) activity serves as a surrogate for HIF-1α-VP2 expression, and can be noninvasively assessed in mice using bioluminescence imaging following vector delivery. Transfection of cultured HL-1 cardiomyocytes with pcTnT-HIF-1α-VP2-TSTA-fluc led to a strong correlation between FLuc and HIF-1α-dependent vascular endothelial growth factor expression ( r <sup>2</sup>=0.88). Intramyocardial delivery of pcTnT-HIF-1α-VP2-TSTA-fluc into infarcted mouse myocardium led to persistent HIF-1α-VP2 expression for 4 weeks, even though it improved neither CD31+ microvessel density nor echocardiographically determined left ventricular systolic function. These results lend support to recent findings of suboptimal efficacy associated with plasmid-mediated HIF-1α therapy. The imaging techniques developed herein should be useful for further optimizing HIF-1α-VP2 therapy in pre-clinical models of myocardial ischemia.
    Human Gene Therapy Methods 08/2013; 24(5). DOI:10.1089/hgtb.2013.028 · 2.44 Impact Factor
  • Cedric M Panje · David S Wang · Jürgen K Willmann
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    ABSTRACT: Ultrasound-mediated gene delivery with microbubbles has emerged as an attractive nonviral vector system for site-specific and noninvasive gene therapy. Ultrasound promotes intracellular uptake of therapeutic agents, particularly in the presence of microbubbles, by increasing vascular and cell membrane permeability. Several preclinical studies have reported successful gene delivery into solid tumors with significant therapeutic effects using this novel approach. This review provides background information on gene therapy and ultrasound bioeffects and discusses the current progress and overall perspectives on the application of ultrasound and microbubble-mediated gene delivery in cancer.
    Investigative radiology 05/2013; 48(11). DOI:10.1097/RLI.0b013e3182982cc1 · 4.44 Impact Factor
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    ABSTRACT: Cutaneous complications can result from nontarget deposition during transcatheter arterial chemoembolization or radioembolization. Liver tu"TACE" because of its inconsistent use in the literature (ie, to abbreviate different terms). Please note that "TACE" has been replaced with "transcatheter arterial chemoembolization" or simply "chemoembolization" as appropriate throughout the manuscript. Please verify these changes.-->mors may receive blood supply from parasitized extrahepatic arteries (EHAs) that also perfuse skin or from hepatic arteries located near the origin of the falciform artery (FA), which perfuses the anterior abdominal wall. To vasoconstrict cutaneous vasculature and prevent nontarget deposition, ice packs were topically applied to at-risk skin in nine chemoembolization treatments performed via 14 parasitized EHAs, seven chemoembolization treatments near the FA origin, and five radioembolization treatments in cases in which the FA could not be prophylactically coil-embolized. No postprocedural cutaneous complications were encountered.
    Journal of vascular and interventional radiology: JVIR 04/2013; 24(4):596-600. DOI:10.1016/j.jvir.2012.12.020 · 2.41 Impact Factor
  • David S Wang · John D Louie · Daniel Y Sze
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    ABSTRACT: Intra-arterial therapies for unresectable hepatic metastases from colorectal cancer include radioembolization (RE) with yttrium-90 microspheres, transarterial chemoembolization (TACE), hepatic arterial infusion, and percutaneous hepatic perfusion using an organ isolation system. In this article, we discuss our approach toward treatment selection, followed by details of how RE and TACE are performed at our institution.
    Seminars in Interventional Radiology 03/2013; 30(1):12-20. DOI:10.1055/s-0033-1333649
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    ABSTRACT: Objective: To assess the effect of varying microbubble (MB) and DNA doses on the overall and comparative efficiencies of ultrasound (US)-mediated gene delivery (UMGD) to murine hindlimb skeletal muscle using cationic versus neutral MBs. Materials and Methods: Cationic and control neutral MBs were characterized for size, charge, plasmid DNA binding, and ability to protect DNA against endonuclease degradation. UMGD of a codon optimized firefly luciferase (Fluc) reporter plasmid to endothelial cells (1 MHz, 1 W/cm², 20% duty cycle, 1 min) was performed in cell culture using cationic, neutral, or no MBs. In vivo UMGD to mouse hindlimb muscle was performed by insonation (1 MHz, 2 W/cm², 50% duty cycle, 5 min) after intravenous administration of Fluc combined with cationic, neutral, or no MBs. Gene delivery efficiency was assessed by serial in vivo bioluminescence imaging. Efficiency of in vivo UMGD with cationic versus neutral MBs was systematically evaluated by varying plasmid DNA dose (10, 17.5, 25, 37.5, and 50 µg) while maintaining a constant MB dose of 1x108 MBs and by changing MB dose (1x107, 5x107, 1x108, or 5x108 MBs) while keeping a constant DNA dose of 50 µg. Results: Cationic and size-matched control neutral MBs differed significantly in zeta potential with cationic MBs being able to bind plasmid DNA (binding capacity of 0.03 pg/MB) and partially protect DNA from nuclease degradation while neutral MBs could not. Cationic MBs enhanced UMGD compared to neutral MBs as well as no MB and no US controls both in cell culture (P < 0.001) and in vivo (P < 0.05). Regardless of MB type, in vivo UMGD efficiency increased dose-dependently with DNA dose and showed overall maximum transfection with 50 µg DNA. However, there was an inverse correlation (ρ = -0.90; P = 0.02) between DNA dose and the degree of enhanced UMGD efficiency observed with using cationic MBs instead of neutral MBs. The delivery efficiency advantage associated with cationic MBs was most prominent at the lowest investigated DNA dose (7.5-fold increase with cationic versus neutral MBs at a DNA dose of 10 µg; P = 0.02) compared to only a 1.4-fold increase at a DNA dose of 50 µg (P < 0.01). With increasing MB dose, overall in vivo UMGD efficiency increased dose-dependently with a maximum reached at a dose of 1x108 MBs with no further significant increase with 5x108 MBs (P = 0.97). However, compared to neutral MBs, cationic MBs enhanced UMGD efficiency the most at low MB doses. Relative enhancement of UMGD efficiency using cationic over neutral MBs decreased from a factor of 27 for 1x107 MBs (P = 0.02) to a factor of 1.4 for 1x108 MBs (P < 0.01) and no significant difference for 5x108 MBs. Conclusions: Cationic MBs enhance UMGD to mouse skeletal muscle relative to neutral MBs but this is dependent on MB and DNA dose. The enhancement effect of cationic MBs on UMGD efficiency is more evident when lower doses of MBs or DNA are used, whereas the advantage of cationic MBs over neutral MBs is substantially reduced in the presence of excess MBs or DNA.
    Theranostics 11/2012; 2(11):1078-91. DOI:10.7150/thno.4240 · 8.02 Impact Factor
  • Jeanne C Lammering · David S Wang · Lewis K Shin
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    ABSTRACT: Heparin-induced thrombocytopenia (HIT) is a life-threatening complication of heparin administration. Of the few reported cases of HIT-associated intra-abdominal thrombosis, none to our knowledge provide multidetector-row computed tomography (MDCT) imaging findings or emphasize its utility in diagnosis. We describe a case of HIT with MDCT images demonstrating extensive intra-abdominal thrombosis and end-organ complications including splenic rupture and pulmonary emboli. This case emphasizes the potential role of MDCT in the rapid detection of HIT-related thromboembolic complications in patients with nonspecific abdominal pain.
    Clinical imaging 11/2012; 36(6):865-8. DOI:10.1016/j.clinimag.2012.01.011 · 0.81 Impact Factor
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    ABSTRACT: To test whether plasmid-binding cationic microbubbles (MBs) enhance ultrasound-mediated gene delivery efficiency relative to control neutral MBs in cell culture and in vivo tumors in mice. Animal studies were approved by the institutional animal care committee. Cationic and neutral MBs were characterized in terms of size, charge, circulation time, and DNA binding. Click beetle luciferase (CBLuc) reporter plasmids were mixed with cationic or neutral MBs. The ability of cationic MBs to protect bound plasmids from nuclease degradation was tested by means of a deoxyribonuclease (DNase) protection assay. Relative efficiencies of ultrasound-mediated transfection (ultrasound parameters: 1 MHz, 1 W/cm(2), 20% duty cycle, 1 minute) of CBLuc to endothelial cells by using cationic, neutral, or no MBs were compared in cell culture. Ultrasound-mediated gene delivery to mouse hind limb tumors was performed in vivo (n = 24) with insonation (1 MHz, 2 W/cm(2), 50% duty cycle, 5 minutes) after intravenous administration of CBLuc with cationic, neutral, or no MBs. Tumor luciferase activity was assessed by means of serial in vivo bioluminescence imaging and ex vivo analysis. Results were compared by using analysis of variance. Cationic MBs (+15.8 mV; DNA binding capacity, 0.03 pg per MB) partially protected bound DNA from DNase degradation. Mean CBLuc expression of treated endothelial cells in culture was 20-fold higher with cationic than with neutral MBs (219.0 relative light units [RLUs]/µg protein ± 92.5 [standard deviation] vs 10.9 RLUs/µg protein ± 2.7, P = .001) and was significantly higher (P < .001) than that in the no MB and no ultrasound control groups. Serial in vivo bioluminescence of mouse tumors was significantly higher with cationic than with neutral MBs ([5.9 ± 2.2] to [9.3 ± 5.2] vs [2.4 ± 0.8] to [2.9 ± 1.1] × 10(4) photons/sec/cm(2)/steradian, P < .0001) and versus no MB and no ultrasound controls (P < .0001). Results of ex vivo analysis confirmed these results (ρ = 0.88, P < .0001). Plasmid-binding cationic MBs enhance ultrasound-mediated gene delivery efficiency relative to neutral MBs in both cell culture and mouse hind limb tumors.
    Radiology 06/2012; 264(3):721-32. DOI:10.1148/radiol.12112368 · 6.87 Impact Factor
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    ABSTRACT: Glioblastoma multiforme (GBM) is the most common and lethal primary brain tumor in adults. We combined neuroimaging and DNA microarray analysis to create a multidimensional map of gene-expression patterns in GBM that provided clinically relevant insights into tumor biology. Tumor contrast enhancement and mass effect predicted activation of specific hypoxia and proliferation gene-expression programs, respectively. Overexpression of EGFR, a receptor tyrosine kinase and potential therapeutic target, was also directly inferred by neuroimaging and was validated in an independent set of tumors by immunohistochemistry. Furthermore, imaging provided insights into the intratumoral distribution of gene-expression patterns within GBM. Most notably, an "infiltrative" imaging phenotype was identified that predicted patient outcome. Patients with this imaging phenotype had a greater tendency toward having multiple tumor foci and demonstrated significantly shorter survival than their counterparts. Our findings provide an in vivo portrait of genome-wide gene expression in GBM and offer a potential strategy for noninvasively selecting patients who may be candidates for individualized therapies.
    Proceedings of the National Academy of Sciences 05/2008; 105(13):5213-8. DOI:10.1073/pnas.0801279105 · 9.67 Impact Factor
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    ABSTRACT: Vascular endothelial growth factor-121 (VEGF121), an angiogenic protein secreted in response to hypoxic stress, binds to VEGF receptors (VEGFRs) overexpressed on vessels of ischemic tissue. The purpose of this study was to evaluate 64Cu-VEGF121 positron emission tomography for noninvasive spatial, temporal, and quantitative monitoring of VEGFR2 expression in a murine model of hindlimb ischemia with and without treadmill exercise training. 64Cu-labeled VEGF121 and a VEGF mutant were tested for VEGFR2 binding specificity in cell culture. Mice (n=58) underwent unilateral ligation of the femoral artery, and postoperative tissue ischemia was assessed with laser Doppler imaging. Longitudinal VEGFR2 expression in exercised and nonexercised mice was quantified with 64Cu-VEGF121 positron emission tomography at postoperative day 8, 15, 22, and 29 and correlated with postmortem gamma-counting. Hindlimbs were excised for immunohistochemistry, Western blotting, and microvessel density measurements. Compared with the VEGF mutant, VEGF121 showed specific binding to VEGFR2. Perfusion in ischemic hindlimbs fell to 9% of contralateral hindlimb on postoperative day 1 and recovered to 82% on day 29. 64Cu-VEGF121 uptake in ischemic hindlimbs increased significantly (P < 0.001) from a control level of 0.61+/-0.17% ID/g (percentage of injected dose per gram) to 1.62+/-0.35% ID/g at postoperative day 8, gradually decreased over the following 3 weeks (0.59+/-0.14% ID/g at day 29), and correlated with gamma-counting (R2 = 0.99). Compared with nonexercised mice, 64Cu-VEGF121 uptake was increased significantly (P < or = 0.0001) in exercised mice (at day 15, 22, and 29) and correlated with VEGFR2 levels as obtained by Western blotting (R2 = 0.76). Ischemic hindlimb tissue stained positively for VEGFR2. In exercised mice, microvessel density was increased significantly (P<0.001) compared with nonexercised mice. 64Cu-VEGF121 positron emission tomography allows longitudinal spatial and quantitative monitoring of VEGFR2 expression in murine hindlimb ischemia and indirectly visualizes enhanced angiogenesis stimulated by treadmill exercise training.
    Circulation 02/2008; 117(7):915-22. DOI:10.1161/CIRCULATIONAHA.107.733220 · 14.43 Impact Factor
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    ABSTRACT: To assess the relative efficacy of three compression adjuncts -- D-Stat Dry (D-Stat), QR Powder (QR), and XS Powder (XS) -- for reducing time to hemostasis in patients who underwent diagnostic and interventional percutaneous procedures. D-Stat, QR, or XS was applied in 176 percutaneous diagnostic arterial, therapeutic arterial, venous, and arteriovenous dialysis access (AVDA) procedures in 138 patients. The mean time to hemostasis and application-related complications were retrospectively assessed. Mean time to hemostasis was significantly reduced in all applications of QR (3.1 minutes +/- 1.1) and XS (3.7 minutes +/- 1.1) relative to D-Stat (6.2 minutes +/- 1.1, P < .001 vs both). For therapeutic arterial procedures, mean time to hemostasis for QR and XS was 3.6 minutes +/- 1.1 and 4.8 minutes +/- 1.1, respectively, and this was significantly less than that of D-Stat (10.0 minutes +/- 1.2; P < .001 vs QR, P < .01 vs XS). Mean times to hemostasis for QR and XS were also shorter than that with D-Stat in diagnostic arterial and AVDA procedures (P < .05). For venous procedures, mean time to hemostasis for QR (1.9 minutes +/- 1.2) was significantly shorter than that with both D-Stat (4.0 minutes +/- 1.2, P < .05) and XS (3.7 minutes +/- 1.2, P < .05). Minor immediate complications (hematoma <5 cm) occurred in 2.8% of applications. No access site infections were observed. All three agents effectively reduced time to hemostasis with minimal associated complications. QR was found to be more effective than D-Stat in all four procedure types.
    Journal of Vascular and Interventional Radiology 01/2008; 19(1):72-9. DOI:10.1016/j.jvir.2007.08.028 · 2.41 Impact Factor
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    David S Wang · Michael D Dake · Jinha M Park · Michael D Kuo
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    ABSTRACT: The characterization of human diseases by their underlying molecular and genomic aberrations has been the hallmark of molecular medicine. From this, molecular imaging has emerged as a potentially revolutionary discipline that aims to visually characterize normal and pathologic processes at the cellular and molecular levels within the milieu of living organisms. Molecular imaging holds promise to provide earlier and more precise disease diagnosis, improved disease characterization, and timely assessment of therapeutic response. This primer is intended to provide a broad overview of molecular imaging with specific focus on future clinical applications relevant to interventional radiology.
    Journal of Vascular and Interventional Radiology 10/2006; 17(9):1405-23. DOI:10.1097/01.RVI.0000235746.86332.DF · 2.41 Impact Factor
  • Michael D Dake · David S Wang
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    ABSTRACT: Endovascular stent grafts are now accepted globally and approved by the US Food and Drug Administration as an alternative to open surgical repair for patients with descending thoracic aortic aneurysm. However, as opposed to the abdominal aorta, application of this technology to manage thoracic aortic disease is not limited to degenerative aneurysms. In fact, international registries and surveys estimate that only 60% of the thoracic cases managed currently with stent-graft placement are aneurysms. The remainder of this experience includes acute dissection, chronic dissection, traumatic aortic injury, penetrating ulcer, intramural hematoma, aortic fistula, anastomotic pseudoaneurysm, and an embolizing lesion. In this regard, it is important to keep in mind that the present devices used in these nonaneurysmal applications are not designed to address the unique anatomical and pathological features that these lesions present. Consequently, in the future, it is possible that we will see stent-graft designs that focus specifically on the challenges of some of the nonaneurysmal thoracic aortic pathologies.
    Seminars in Vascular Surgery 04/2006; 19(1):40-7. DOI:10.1053/j.semvascsurg.2005.11.007 · 1.38 Impact Factor
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    ABSTRACT: To test the hypothesis that controlled perivascular release of tissue plasminogen activator (tPA) can generate cleaved extracellular matrix (ECM) chemotactic gradients to guide the migration of vascular smooth muscle cells (SMCs) away from the lumen, thereby limiting neointima formation. This hypothesis was tested in rabbit models in which the perivascular surface of vein bypass grafts was treated with microspheres releasing tPA (MS-tPA), microspheres containing no drug (MS-blank), or phosphate buffered saline (PBS). Vein graft segments harvested after 7 days were then evaluated for elastin content, proliferating SMCs, intima-to-media (I/M) ratio, and inflammation; late impact on neointima formation was also examined. The 7-day results demonstrated cleaved elastin gradients and proliferating SMCs that assumed a more peripheral distribution in the MS-tPA group than MS-blank and PBS controls (p<0.05). At 28 days, vein grafts treated with MS-tPA showed a mean I/M ratio (0.35+/-0.04) that was 63.5% lower than PBS controls (0.96+/-0.07, p<0.005) and 43.5% lower than MS-blank specimens (0.62+/-0.08, p<0.05). Perivascular release of tPA modifies ECM gradients, directionally guides SMC migration away from the lumen, and limits neointima formation.
    Journal of Endovascular Therapy 01/2006; 12(6):667-75. DOI:10.1583/04-1268Ra.1 · 3.35 Impact Factor
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    Circulation 10/2005; 112(11):1663-75. DOI:10.1161/CIRCULATIONAHA.105.541284 · 14.43 Impact Factor
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    ABSTRACT: To examine the effects of oxidative stress on neointimal hyperplasia through local overexpression of human copper-zinc superoxide dismutase (Cu-Zn SOD). The left common femoral arteries (CFA) of 18 New Zealand white rabbits were subjected to balloon overdilation injury. Each dilated CFA was then incubated with either a nonviral (buffer) or viral (adenovirus overexpressing beta-galactosidase) control or an adenovirus overexpressing Cu-Zn SOD. Animals were then sacrificed at 3, 7, or 28 days (3 arteries per group per time point) and the treated CFA segments were harvested for analysis of esterase-positive inflammatory cells and extracellular matrix elements. The intima-to-media ratio (I/M) was measured to assess the degree of neointimal formation. At 3 days, local SOD levels in the Cu-Zn SOD-treated group were significantly elevated relative to both controls (p<0.01). Significant reductions in lipid peroxidation byproducts were also seen in the SOD group relative to viral and nonviral controls (p<0.05). Mean I/M at 28 days was 0.582+/-0.088 for the nonviral control group versus 0.565+/-0.133 for the viral control group. The SOD-treated group had a significant reduction relative to both controls: 0.259+/-0.045 (p<0.05). Statistically significant reductions in I/M were also demonstrated in the SOD group relative to control groups at 7 days (p<0.05). The SOD-treated group demonstrated significant preservation of elastin relative to controls, as well as a significant reduction in esterase-positive granulocytes relative to controls (p<0.05). Direct buffering of oxidative stress in balloon-injured vessels can significantly alter postinjury response and limit neointimal hyperplasia.
    Journal of Endovascular Therapy 01/2005; 11(6):585-94. DOI:10.1583/04-1310.1 · 3.35 Impact Factor
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    ABSTRACT: To evaluate effect of controlled stent-based release of an NO donor to limit in-stent restenosis in rabbits. Bioerodable microspheres containing NO donor or biodegradable polymer (polylactide-co-glycolide-polyethylene glycol) were prepared and loaded in channeled stents. Daily concentrations of NO release from NO-containing microspheres were assayed in vitro. NO- and polymer-containing (control) microsphere-loaded stents were deployed in aortas of New Zealand white rabbits (n = 8). Aortas with stents were harvested at 7 (n = 5) and 28 days (n = 3) and evaluated for cyclic guanosine monophosphate (cGMP) levels (7 days), number of proliferating cell nuclear antigen-positive cells (7 days), and intima-to-media ratio (7 and 28 days), with statistical significance evaluated by using one-way analysis of variance. NO-containing microspheres released NO with an initial bolus in the 1st week, followed by sustained release for the remaining 3 weeks. Significant increase in cGMP levels and decrease in proliferating cell nuclear antigen-positive cells were found at 7 days for the NO-treated group relative to controls (P <.05). Intima-to-media ratio in the NO-treated group was reduced by 46% and 32% relative to controls at 7 and 28 days, respectively (mean, 0.14 +/- 0.01 [standard error] vs 0.26 +/- 0.02 at 7 days, P <.01; 1.34 +/- 0.05 vs 1.98 +/- 0.08 at 28 days, P <.01). Stent-based controlled release of NO donor significantly reduces in-stent restenosis and is associated with increase in vascular cGMP and suppression of proliferation.
    Radiology 02/2004; 230(2):377-82. DOI:10.1148/radiol.2302020417 · 6.87 Impact Factor

Publication Stats

306 Citations
86.06 Total Impact Points


  • 2012–2013
    • Stanford Medicine
      • Department of Radiology
      Stanford, California, United States
  • 2004–2013
    • Stanford University
      • Division of Interventional Radiology
      Palo Alto, California, United States
  • 2006–2008
    • University of California, San Diego
      San Diego, California, United States