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Biomedical subjects

Ron Waksman

Publications and source records attributed to Ron Waksman.

At least 199 records · Page 11Linked to original sources
PubMedDate not supplied

IVUS-based dosimetry on patients with repeat-radiated coronary arteries to the same site.

BACKGROUND AND PURPOSE: Intracoronary radiation reduces recurrent in-stent restenosis (ISR). Repeat radiation may become necessary due to recurrent ISR. This study reports outcome-related dose calculations for twice-radiated coronary artery segments. MATERIALS AND METHODS: A total of 22 patients with angiographic evidence of ISR in a previously treated native coronary artery were assigned for repeat percutaneous coronary intervention and intravascular brachytherapy (IVBT). Intravascular brachytherapy was performed either with a 192Ir- or a 90Sr/Y-source (prescription dose: 14-18 and 23 Gy each at 2 mm from the center of the source), or a 32P-source (20 Gy 1-mm deep to the vessel wall). The mean time interval between the two IVBT treatments was 394+/-306 days. For each patient, angiograms and intravascular ultrasound cross sections were reviewed, on the basis of anatomical landmarks, matched, and the twice-radiated vessel segment identified. RESULTS: Clinical follow-up at 379+/-146 days revealed a target vessel revascularization rate of 18.2% and a target lesion revascularization rate of 13.6%. One death was reported. Maximal dose and average dose at the endothelium were 261 and 124+/-72.3 Gy, and maximal dose and average dose at the adventitia-media border were 159 and 50.3+/-29.3 Gy. Fourteen patients had 1.71 times longer recurrence-free interval compared to the interval between both IVBT treatments. CONCLUSIONS: Repeat IVBT to the same ISR site is safe without any adverse clinical events at an average 12 months' follow-up. A second IVBT treatment led to a prolonged ISR-free survival for the majority of patients. The choice of isotope did not influence outcome.

Beta Particles↗
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Bivalirudin versus unfractionated heparin in patients undergoing percutaneous coronary intervention after acute myocardial infarction.

BACKGROUND: Bivalirudin is replacing heparin as the anticoagulant agent of choice for elective percutaneous coronary intervention (PCI). This study aimed to assess the safety and clinical outcomes of bivalirudin versus unfractionated heparin (UFH) in patients undergoing PCI for acute myocardial infarction (AMI). METHODS: A cohort of 672 consecutive patients presenting with AMI without prior thrombolytic therapy were treated with either bivalirudin (216 patients) or UFH (456 patients). Platelet glycoprotein IIb/IIIa inhibitors were administered at the operator's discretion. The in-hospital, 30-day, and 6-month outcomes of the two groups were compared. RESULTS: Baseline clinical and angiographic characteristics were similar between the groups. In-hospital complications were similar, although there was a trend of a less major hematocrit drop in the bivalirudin group (0.9% vs. 3.1%, P=.09). All clinical outcomes were similar between the groups at 30-day and 6-month follow-ups. There was no statistical significance for acute thrombosis and subacute thrombosis between the groups, and there was no late thrombosis from either group. The event-free survival rate was similar between the groups (P=.41). CONCLUSION: The use of bivalirudin in patients undergoing PCI after AMI is safe and feasible. Bivalirudin should be considered as an alternative anticoagulant agent during PCI to treat patients presenting with AMI.

Aged↗
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Optimal dosing and duration of oral everolimus to inhibit in-stent neointimal growth in rabbit iliac arteries.

BACKGROUND: Everolimus is an orally active derivative of sirolimus. Oral administration of rapamycin is efficacious in the reduction of neointima formation and clinical restenosis; however, its optimal dose and duration have not been determined. METHODS: New Zealand White rabbits were divided into three groups. The first (low-dose) group received 1.5 mg/kg everolimus 1 day before stenting, followed by 0.75 mg/kg/day everolimus for 28 days. The second (high-dose) group received 6 mg/kg everolimus 1 day before, on the day of, and on the day after stenting, followed by 2 mg/kg/day for 4 days. The third (placebo) group received a matching volume of vehicle similar to that of Group 2. Twenty-eight days after stenting, animals were euthanized and morphometry was performed. RESULTS: In the high-dose group, circulating everolimus levels corresponded with administrated dose levels; by Day 12, no circulating everolimus could be detected. In the low-dose everolimus group, levels remained constant up to 28 days. When compared with placebo, low-dose everolimus was associated with a significant reduction in medial thickness (32%), neointimal area (60%), and percent stent stenosis (33%); however, high-dose everolimus had no significant effect. CONCLUSIONS: In conclusion, oral everolimus suppresses in-stent neointimal growth in rabbit iliac arteries. Four weeks of low-dose everolimus is more effective than 7 days of high-dose everolimus.

Administration, Oral↗
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Bone marrow-derived stem cell interactions with adult cardiomyocytes and skeletal myoblasts in vitro.

BACKGROUND AND OBJECTIVES: Secreted growth factors and cell-to-cell contact are both required to elicit cellular functions. We tested the hypothesis that bone-marrow-derived growth factors, together with cell-to-cell contact between bone-marrow-derived stem cells and cardiomyocytes or myoblasts, promote the proliferation of cardiomyocytes and myoblasts. METHODS: Human cardiomyocytes or skeletal myoblasts were cultured for 4 days in the presence of low and high concentrations of bone-marrow-derived mononuclear cell conditioned medium (MNC-CM) or marrow stromal cell conditioned medium (MSC-CM). The concentrations of vascular endothelial growth factor (VEGF), monocyte chemoattractant protein-1 (MCP-1), hepatocyte growth factor (HGF), and insulin-like growth factor-1 in their respective conditioned media were assayed by enzyme-linked immunosorbent assay. Stem cells were mixed with cardiomyocytes or skeletal myoblasts at a 1:1 ratio and cultured for 7 days to assess the proliferation of these cells. In parallel experiments, equal numbers of various cell types were cultured alone. RESULTS: The concentrations of VEGF, MCP-1, and HGF increased in MNC-CM and MSC-CM. MNC-CM showed no effect on cardiomyocyte proliferation. A low concentration of MSC-CM increased cardiomyocyte proliferation by 60% (P<.05). Low concentrations of MNC-CM or MSC-CM showed a trend toward an increased proliferation of myoblasts. A high concentration of either conditioned medium showed a toxic effect. In contact coculture, the proliferation of cardiomyocytes and MNC showed no synergistic effect; instead, there was some evidence of inhibition. The proliferation of cardiomyocytes and stromal cells showed an additive effect. Myoblasts in contact coculture with MNC or MSC showed no synergistic effect. CONCLUSION: These in vitro results suggest that paracrine effects may be the mechanism by which stromal cells become beneficial in cardiac therapy. MNC do not induce the proliferation of cardiomyocytes. Stem-cell-secreted growth factors induce the proliferation of myoblasts, which is not influenced by cell-to-cell contact.

Analysis of Variance↗
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Comparison of paclitaxel-eluting stent and sirolimus-eluting stent expansion at incremental delivery pressures.

OBJECTIVES: We sought to compare the adequacy of paclitaxel-eluting stent (PES) and sirolimus-eluting stent (SES) expansion based on intravascular ultrasound (IVUS) imaging criteria at conventional delivery pressures. METHODS: Forty-six patients underwent SES implantation and 42 patients underwent PES implantation for de novo native coronary lesions<33 mm in length with reference lumen diameters of 2.5-3.5 mm. Stents were serially expanded with gradual balloon inflations at 14 and 20 atm. IVUS imaging was performed prior to intervention and after each balloon inflation. Stent expansion (minimal stent cross-sectional area/reference lumen cross-sectional area) was measured. Inadequate stent expansion was defined using the MUSIC criteria (all struts apposed, no tissue protrusion, and final lumen cross-sectional area>80% of the reference or >90% if minimal lumen cross-sectional area was <9 mm2). RESULTS: The baseline characteristics of the two groups were similar except for shorter lesion length, larger mean lumen cross-sectional area, larger lumen diameter, and lower plaque burden in the PES group. Stent expansion was inadequate in 80% of patients with SES versus 63% of patients with PES at 14 atm, although this was not statistically significant. After 20 atm, 48% of patients with SES remained underexpanded as compared with 35% of patients with PES. CONCLUSION: Drug-eluting stents showed significant underexpansion by MUSIC criteria at conventionally used inflation pressures. Higher balloon inflations are required especially during deployment of a SES. IVUS guidance is recommended to ensure optimal results and outcomes with both stents.

Aged↗
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Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy.

Although the safety profiles of coronary stents eluting sirolimus or paclitaxel do not seem to differ from those of bare metal stents in the short-to-medium term, concern has arisen about the potential for late stent thromboses related to delayed endothelialisation of the stent struts. We report four cases of angiographically-confirmed stent thrombosis that occurred late after elective implantation of polymer-based paxlitaxel-eluting (343 and 442 days) or sirolimus-eluting (335 and 375 days) stents, and resulted in myocardial infarction. All cases arose soon after antiplatelet therapy was interrupted. If confirmed in systematic long-term follow-up studies, our findings have potentially serious clinical implications.

Aged↗
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Safety and efficacy of manual stepping and overlapping of beta-emitter for diffuse in-stent restenosis lesions.

BACKGROUND: The effects of overlapping beta-emitter sources on the treatment of in-stent restenosis (ISR) lesions as a result of manual stepping are unknown. METHODS AND RESULTS: In the BETA WRIST (Beta Washington Radiation for In-stent Restenosis Trial), 17 out of the 50 patients who received radiation treatment had diffuse ISR in native coronaries that required manual stepping of the beta-emitter (90Y) source in order to cover the lesion and the edges. Fourteen of those patients received radiation with an overlap of up to 3 mm in the middle of the stented segment. The prescribed dose was 20.6 Gy to a distance of 1.0 mm from the surface of the inflated balloon, and the calculated dose to the vessel wall at the overlapped area did not exceed 75 Gy. There was no difference in late total occlusion (7.1% vs. 9.0%, P=NS) and target lesion revascularization (28.5% vs. 27.2%, P=NS) between patients with stepping and those without stepping. At 6 months, there was no evidence of perforation or aneurysm at the overlapped segments. Quantitative coronary angiographic (QCA) analysis revealed significantly reduced late loss in the overlapped segment compared to the adjacent segment (P=.04). Serial (postradiation vs. follow-up) IVUS measurement showed larger mean lumen cross-sectional area (CSA) (P=.0035) and smaller mean intimal hyperplasia (IH) CSA (P=.0010) in the overlapped segment compared to the adjacent segment. CONCLUSION: Manual stepping of beta-emitter source with a short overlapped segment is safe for diffuse ISR. Further increase in lumen dimension and reduction in IH formation are observed at the overlapped segment.

Adult↗
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The cost-effectiveness of beta-radiation therapy for treatment of in-stent restenosis: an analysis at 290-day follow-up.

PURPOSE: We studied the cost-effectiveness of percutaneous coronary intervention (PCI) plus beta-radiation (Radiotherapy) vs. PCI alone for treating in-stent restenosis. METHODS AND MATERIALS: We analyzed medical resource data collected at US sites during the Intimal Hyperplasia Inhibition with beta In-stent Trial (INHIBIT) to compare the incremental costs between Radiotherapy and PCI alone for each repeat target lesion revascularization (TLR) avoided. Costs were assigned for cardiac-related medical services using the Medicare payer perspective. RESULTS: Radiotherapy increased initial inpatient costs by US$3360 (P<.001). In the Radiotherapy and PCI alone groups, the mean per-patient rates for TLR were 0.13 vs. 0.30 (P=.001), and mean per-patient total costs were US$19,286 vs. US$18,349 (P<.001), respectively. The incremental cost of Radiotherapy relative to PCI alone was US$5512 per TLR avoided, which compares favorably to the observed mean per-patient cost of treating restenosis (US$16,852). CONCLUSIONS: beta-radiation is a cost-effective adjunct to PCI in treating patients with in-stent restenosis.

Aged↗
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The initial course of in-stent restenosis influences the response to vascular brachytherapy.

BACKGROUND: Vascular brachytherapy (VBT) reduces the rate of recurrence of in-stent restenosis (ISR) by inhibiting intimal proliferation. However, the rate of cell proliferation, reflected by the speed of ISR development, is variable in ISR lesions and might influence the responsiveness of ISR to radiation. The aim of this study was to determine the influence of the initial ISR course on the clinical outcome of patients undergoing VBT. METHODS: In 1165 patients treated for ISR with VBT in the WRIST studies, we determined the time for ISR (time between initial stent implantation and restenosis), the time for VBT treatment (time between stent implantation and VBT), and previous ISR treatment with conventional strategies. Target lesion revascularization (TLR) at 6 months was available in all patients. RESULTS: Previous ISR treatment did not influence the result of VBT (TLR was 17% vs. 16% without previous angioplasty). Time to ISR influences the outcome of patients undergoing VBT; TLR decreased when ISR occurred later. TLR was 18.2%, 16.7%, and 11.1% when time to ISR was <90, 90-2700, and >270 days, respectively, P=.03. Early ISR (time for ISR <90 days) is a factor for radiation failure (OR=2.1, P<.05). In patients with early ISR, TLR is lower when VBT is delayed; TLR was 11% if performed 90 days after stent implantation as compared to 22% if VBT is performed early (<90 days), P<.05. CONCLUSION: The course of ISR development affects the long-term efficacy of VBT. Early restenosis remains a factor of treatment failure in the VBT era. Delaying VBT beyond 90 days after stent implantation reduces the rate of subsequent revascularization in these patients.

Aged↗
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Five-year clinical and angiographic follow-up after intracoronary iridium-192 radiation therapy.

BACKGROUND: Ionizing gamma radiation has been shown to reduce neointimal formation and the incidence of restenosis after balloon angioplasty and stenting in clinical trials. However, the long-term effects of this therapy are unknown. The first cohort of patients to receive intracoronary gamma radiation after balloon angioplasty for the prevention of restenosis have completed a 5-year angiographic and clinical follow-up. The outcome of these patients is presented and discussed. METHODS: Twenty-one patients with unstable angina (22 arteries) underwent standard balloon angioplasty. Intracoronary radiation therapy was performed immediately after the intervention using an Iridium-192 source wire hand-delivered to the angioplasty site. All patients were followed clinically and Quantitative Coronary Analysis (QCA) was performed at 6, 24, 36 and 60 months. RESULTS: Target lesion revascularization occurred in six lesions, three of which were total occlusions (two early within 30 days and one occurred at 2 years), and one patient had a myocardial infarction attributable to a nontarget vessel. Serial QCA detected a binary restenosis rate of 28.6% (n=6) at 6 months. The late loss (0.29 mm) and loss index (0.25) remained low at 2, 3 and 5 years. Angiographic complications included four aneurysms (two procedure related and two occurring within 3 months). At 2 years, only one aneurysm increased in size (46 vs. 27 mm(2)); and at 3 and 5 years, all aneurysms remained unchanged. No other angiographic complications were observed. CONCLUSION: The early clinical and angiographic effects of intracoronary gamma radiation were maintained at 5 years without further increase in the aneurysm formation or apparent new adverse effects related to the radiation therapy between 2 and 5 years.

Adult↗
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The proximal location of stenosis in the left anterior descending coronary artery is not a predictive factor of worse outcome in the era of the stent.

BACKGROUND: Patients treated for lesions in the proximal left anterior descending coronary artery (P-LAD) have worse outcome after balloon angioplasty as compared to patients treated for lesions in the distal left anterior descending coronary artery (D-LAD). We sought to examine if this discrepancy was still observed after stenting. METHODS: A total of 676 consecutive patients with a symptomatic monovessel disease in the LAD artery who underwent angioplasty with stenting were prospectively entered into a dedicated database. Among this cohort, 322 lesions were located in P-LAD and 354 in D-LAD. Patients with total occlusion, acute myocardial infarction (MI) or restenosis were excluded. RESULTS: Procedural characteristics were similar in the two groups. Procedural success was high with the same rates of in-hospital death and Q-wave MI for patients treated in P-LAD and D-LAD. At 1 year, the rate of target lesion revascularization (TLR) was 13.9% in the P-LAD group and 16.3% in the D-LAD group (P = .79), and the rate of event-free survival was 81.9% and 81% (P = .67), respectively. The treatment of ostial lesions (n = 23) was not related to worse outcome. In multivariate analysis, lesion location was not a predictor of major adverse cardiac events (MACE). CONCLUSION: This study shows that stenting of lesions in the P-LAD is as effective and safe as treatment of lesions located in D-LAD. Therefore, when stenting is feasible, the location of the lesion in the LAD is not predictive of worse outcome and, consequently, should not be taken into account in the choice of the revascularization strategy.

Aged↗
PubMedDate not supplied

Dose volume histogram assessment of late stent malapposition after intravascular brachytherapy.

PURPOSE: Positive remodeling and decreased neointima proliferation are among the causes for Late Stent Malapposition (LSM). It was our interest to investigate a possible relationship between dose and incidence of LSM. METHODS: Index and follow up IVUS examinations of 238 patients (152 treated with Intravascular Brachytherapy (IVBT), 86 control) enrolled in IVBT trials were reviewed to identify patients with LSM. 7.2% of patients treated with IVBT and 2.3% of patients in the control group were found to have LSM on their 6-month follow-up IVUS. Using the index IVUS study. Dose Volume Histograms (DVH) were constructed for a segment of the adventitia comprising an arc deep to the area where LSM is present at follow up. For control, two areas: an arc deep to complete apposition (Control 1) and a segment within the stent but 5 mm apart from the LSM (Control 2). Volumes were defined by IVUS images that were 1 mm apart and the media-adventitial contour was taken to be 0.5 mm thick from the border. RESULTS: DVH of 90% and 50% adventitial volume of LSM area received a significantly (p < .05) higher dose compared to both controls. Calculated are 12 LSM sites in 9 patients and 9 control sites. At all 12 sites Mean Cross Sectional Area of External Elastic Membrane (EEM CSA) was significantly larger in the LSM group at follow up compared to index (p-.001). CONCLUSIONS: DVH analysis showed a positive correlation between radiation dose to the adventitia and incidence of LSM. The myofibroblasts in the adventitia are known to be the target for irradiation. Proliferation of myofibroblasts leads to neointima formation. LSM may be due to the higher dosages delivered to 50% and 90% of the adventitia volume (LSM area) which may have led to profound neointima suppression. In turn the neointima could not compensate positive remodeling reflected by an increase in EEM CSA.

Blood Vessel Prosthesis Implantation↗
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Antioxidants attenuate atherosclerotic plaque development in a balloon-denuded and -radiated hypercholesterolemic rabbit.

BACKGROUND: Oxidation of lipoproteins is considered to be a key contributor to atherogenesis. Antioxidants are potential antiatherogenic agents because they can inhibit lipoprotein oxidation. Radiation has been shown to increase oxidative stress leading to increased atherogenesis. This study is designed to test the potential of antioxidants to inhibit atherosclerotic plaque progression in balloon-denuded and -radiated rabbits. METHODS AND RESULTS: Two groups of New Zealand white rabbits (n=36) were fed with 1% cholesterol diet (control diet) or with 1% cholesterol diet containing a mixture of various antioxidants for 1 week. Iliac arteries in all the animals were balloon denuded and continued to fed with 0.15% cholesterol diet or 0.15% cholesterol diet containing antioxidants (antioxidant diet). Four weeks after balloon denudation one iliac artery in 12 animals from each group was radiated and all the animals were continued to be fed with the same diet. Four weeks after radiation animals were sacrificed and morphometric analysis of iliac arteries (n=12) in nonradiated and radiated animals were performed. Plaque area (PA) in the rabbits that were fed with cholesterol diet is 0.2+/-0.12 mm2, and it is increased by 2.75-fold (P<.05) in the radiated arteries of animals fed with cholesterol diet. Plaque area in the animals fed with antioxidant diet is 50% less then the one in the animals fed with cholesterol diet. Similarly, plaque area in radiated arteries of the animals fed with antioxidant diet is 50% less then the animals fed with cholesterol diet. CONCLUSION: Antioxidants significantly attenuate atherosclerotic plaque progression in balloon-injured and -radiated hypercholesterolemic rabbits.

Animals↗
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Drug-eluting stents: from bench to bed.

The introduction of stents to clinical practice in 1987 was the major breakthrough in the field of percutaneous coronary intervention (PCI). The use of stenting has drastically improved the outcomes of traditional PCI. First stents were approved for bailout and treatment of dissections, reducing dramatically the need for emergent coronary artery bypass grafting (CABG) as a result of vessel closure during PCI. Later stents were proven to reduce the restenosis rate of PCI from 30%-40% with balloon angioplasty to 15%-20% with stents, primarily by eliminating elastic recoil and vascular remodeling as shown by intravascular ultrasound (IVUS) studies. These outcomes have led to a wide acceptance of stenting as the strategy of choice for more than 80% of all PCI procedures performed. The current review focuses on the following topics: (1) strategies in drug selection to reduce neointimal proliferation, (2) stent designs and polymer selection as a platform for drug-eluting stents, (3) review of major preclinical and clinical experimental work performed in the field, and (4) a discussion of the potential and limitations of the technology.

Animals↗
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Acute procedural complications and in-hospital events after percutaneous coronary interventions: eptifibatide versus abciximab.

BACKGROUND: Glycoprotein IIb/IIIa antagonists reduce peri-angioplasty ischemic complications and improve in-hospital outcome in patients undergoing percutaneous coronary interventions (PCI). Prior studies have demonstrated favorable results with both eptifibatide and abciximab. The purpose of this study was to assess whether there are any differences in rates of acute procedural complications and in-hospital events with the use of these two agents. METHODS: A retrospective review of 359 elective PCIs from June 1998 to August 2000 identified 152 PCIs treated with eptifibatide (bolus 180 microg/kg, infusion 2 microg/kg/min for 12-48 h) and 205 PCIs treated with abciximab (bolus 0.25 mg/kg, infusion 10 microg/min for 12 h). All patients received IIb/IIIa antagonists at the initiation of the intervention. RESULTS: The clinical demographics, the angiographic morphology, the indications, and the procedural details were similar in both groups. In the eptifibatide group, the maximum ACT was lower (235+/-45 vs. 253+/-40, P<.0001). The incidence of major procedural and in-hospital events was compared. Eptifibatide and abciximab had similar rates of major complications (death or myocardial infarction) (1.4% vs. 2.9%), repeat PTCA (3.4% vs. 1.9%), and major bleeding (3.3% vs. 4.3%). CONCLUSIONS: Eptifibatide is comparable to abciximab in regards to acute procedural complications and in-hospital events after PCI.

Abciximab↗
PubMedDate not supplied

Oral rapamycin inhibits growth of atherosclerotic plaque in apoE knock-out mice.

INTRODUCTION: Inflammatory and immunological responses of vascular cells are known to play significant roles in atherosclerotic plaque development. Rapamycin with antiinflammatory, immunosuppressive and antiproliferative properties has been shown to reduce neointima formation when coated on stents. This study is designed to test the potential of oral rapamycin to inhibit atherosclerotic plaque development. METHODS: Eight-week-old apoE knock-out mice were fed with 0.25% cholesterol supplemented diet (control diet), control diet containing 50 microg/kg rapamycin (low-dose rapamycin) or 100 microg/kg rapamycin (high-dose rapamycin) for 4 or 8 weeks. Subsets of mice from each group (n=10) were weighed and euthanized. Whole blood rapamycin levels were determined using HPLC-MS/MS, and histological analyses of atherosclerotic lesions in the aortic root were performed. RESULTS: Mice fed with high-dose rapamycin did not gain weight (18.5+/-1.5 vs. 20.6+/-0.9 g, P=.01). Blood levels of rapamycin 117+/-7 pg/ml were detected in the blood of mice fed with high-dose rapamycin for 8 weeks. The plaque area in mice fed with high dose oral rapamycin is significantly less as compared to control (0.168+/-0.008 vs. 0.326+/-0.013 mm2, P=.001 at 4 weeks; 0.234+/-0.013 vs. 0.447+/-0.011 mm2, P=.001 at 8 weeks). Lumen area was inversely proportional to the plaque area. CONCLUSIONS: The results indicate that oral rapamycin is effective in attenuating the progression of atherosclerotic plaque in the mice.

Administration, Oral↗