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Biomedical subjects

Timothy D Henry

Publications and source records attributed to Timothy D Henry.

25 records · Page 2Linked to original sources
PubMed2003

One-year follow-up of direct myocardial gene transfer of vascular endothelial growth factor-2 using naked plasmid deoxyribonucleic acid by way of thoracotomy in no-option patients.

This phase I open label, dose-escalating study shows that gene transfer of vascular endothelial growth factor-2 naked deoxyribonucleic acid by direct myocardial injection by way of thoracotomy in patients with Canadian Cardiovascular Society class 3 or 4 angina is feasible and safe. The procedure is well tolerated, with few major adverse cardiac events at 1 year, and without complications directly related to gene expression. In this prospective, nonblinded study, the procedure is associated with clinical improvement; however, there was no angiographic evidence of angiogenesis and there is a great potential for a sham or placebo effect in the study patients. A randomized phase III trial is underway that will help determine the efficacy of vascular endothelial growth factor-2 gene transfer in "no-option" patients.

Adult↗
PubMed2003

Clinical, angiographic, and interventional follow-up of patients with aortic-saphenous vein graft connectors.

BACKGROUND: The use of aortic connectors for proximal saphenous vein bypass graft anastomoses eliminates the need for aortic clamping during coronary artery bypass grafting (CABG) and may reduce the incidence of stroke in the elderly and in patients with severe aortic atherosclerosis. METHODS AND RESULTS: We studied 74 consecutive patients who received the Symmetry Bypass System aortic connector at the time of CABG. A total of 131 of 144 proximal vein graft anastomoses were performed with this device. The left internal mammary artery was used in 62 patients, and 61 patients had "off-pump" coronary revascularization. A total of 11 patients were readmitted with chest pain consistent with unstable angina 173+/-39 days after CABG. Five of the 11 patients had previous in-stent restenosis before CABG. At angiography, 20 saphenous vein bypass grafts containing 19 connectors were found to have severe stenosis (n=12) or occlusion (n=6) and were treated with angioplasty and stenting or medical therapy. Seven of 11 patients were readmitted 76+/-11 days later with recurrent chest pain and were found to have severe stenosis at the previously stented connector site. Six patients underwent angioplasty followed by brachytherapy. Three of these patients redeveloped chest pain and were readmitted 151+/-71 days later. Two patients were started on oral Rapamune, and one patient underwent redo-CABG. CONCLUSIONS: Eleven of 74 patients who received aortic connectors at the time of CABG developed symptomatically significant stenosis or occlusion at the connector site shortly after CABG, requiring multiple repeat interventions, including brachytherapy.

Aged↗
PubMed2003

The VIVA trial: Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis.

BACKGROUND: Recombinant human vascular endothelial growth factor protein (rhVEGF) stimulates angiogenesis in animal models and was well tolerated in Phase I clinical trials. VIVA (Vascular endothelial growth factor in Ischemia for Vascular Angiogenesis) is a double-blind, placebo-controlled trial designed to evaluate the safety and efficacy of intracoronary and intravenous infusions of rhVEGF. METHODS AND RESULTS: A total of 178 patients with stable exertional angina, unsuitable for standard revascularization, were randomized to receive placebo, low-dose rhVEGF (17 ng x kg(-1) x min(-1)), or high-dose rhVEGF (50 ng x kg(-1) x min(-1)) by intracoronary infusion on day 0, followed by intravenous infusions on days 3, 6, and 9. Exercise treadmill tests, angina class, and quality of life assessments were performed at baseline, day 60, and day 120. Myocardial perfusion imaging was performed at baseline and day 60. At day 60, the change in exercise treadmill test (ETT) time from baseline was not different between groups (placebo, +48 seconds; low dose, +30 seconds; high dose, +30 seconds). Angina class and quality of life were significantly improved within each group, with no difference between groups. By day 120, placebo-treated patients demonstrated reduced benefit in all three measures, with no significant difference compared with low-dose rhVEGF. In contrast, high-dose rhVEGF resulted in significant improvement in angina class (P=0.05) and nonsignificant trends in ETT time (P=0.15) and angina frequency (P=0.09) as compared with placebo. CONCLUSIONS: rhVEGF seems to be safe and well tolerated. rhVEGF offered no improvement beyond placebo in all measurements by day 60. By day 120, high-dose rhVEGF resulted in significant improvement in angina and favorable trends in ETT time and angina frequency.

Adult↗
PubMed2003

Detecting vulnerable plaque using peripheral blood: inflammatory and cellular markers.

The concept of the vulnerable patient has arrived. Enhanced diagnostic methods will eventually permit accurately finding and treating these patients and their disease. Clinical Cardiologists now recognize that coronary atherosclerosis is two pathophysiologically distinct syndromes: stable and unstable. Stable coronary syndromes result from fixed, severe stenoses limiting blood flow and causing secondary myocardial ischemia. The unstable acute coronary syndromes are frequently catastrophic and are pathophysiologically distinct. They result from different cell subsets causing vascular inflammatory syndromes rather than gradual lumen constriction by plaque. Though pathophysiologically distinct, they may show common pathophysiology when a ruptured plaque heals and progressively becomes a critical stenosis. For the present hs-CRP measurement is the strongest correlative factor for future clinical events due to arterial inflammation: myocardial infarction, unstable angina, stroke, and peripheral vascular disease in both diseased and apparently healthy, asymptomatic patients. The CRP plasma level also is the best risk assessment in patients with either stable or unstable angina, long term after myocardial infarction, and in patients undergoing revascularization therapies. One study showed the only independent cardiovascular risk indicators using multivariate, age adjusted and traditional risk analysis were CRP and Total/HDL cholesterol ratio. If CRP, IL-6, and ICAM-1 levels are added to lipid levels, risk assessment can be improved over lipids alone. The prevalence of high-risk subjects in the general population is low, amplifying diagnostic problems for vulnerable plaque. Since no test yet has high sensitivity or specificity, diagnostic errors are high, with many false positives and negatives. Sensitivity or specificity must be increased by developing a risk marker panel, or by simultaneously finding other markers that themselves are highly sensitive and specific for vulnerable plaque.

Arteries↗
PubMed2002

A target-mediated model to describe the pharmacokinetics and hemodynamic effects of recombinant human vascular endothelial growth factor in humans.

BACKGROUND: The Vascular Endothelial Growth Factor (VEGF) in Ischemia for Vascular Angiogenesis (VIVA) trial was a double-blind, placebo-controlled, phase II clinical trial designed to evaluate the safety, efficacy, and pharmacokinetics of combined intracoronary and intravenous infusions of recombinant human vascular endothelial growth factor (rhVEGF(165)) for therapeutic angiogenesis. This study describes the use of a mechanism-based model to characterize the nonlinear kinetics observed after intravenous administration of rhVEGF(165). The model predicts that rhVEGF(165) distribution occurs through both saturable binding to high-affinity receptors and reversible interactions with low-affinity binding sites. METHODS: In this trial, rhVEGF(165) was administered to patients with coronary artery disease at a dose rate of 17 or 50 ng/kg/min by means of intracoronary infusion for 20 minutes, followed by three 4-hour intravenous infusions on days 3, 6, and 9. Pharmacokinetic samples and blood pressure measurements were collected at baseline, during infusion, and for 6 hours after infusion. RESULTS: The plasma clearance, steady-state volume of distribution, and terminal half-life after a 4-hour intravenous infusion of rhVEGF(165) at the high dose were 19.1 +/- 5.7 mL/min/kg, 960 +/- 260 mL/kg, and 33.7 +/- 13 minutes, respectively. The duration of hypotension that occurred after rhVEGF(165) administration appeared to be related to the model-predicted VEGF(165) concentration associated with the high-affinity receptor compartment. CONCLUSIONS: This mechanism-based model accurately predicted VEGF concentrations and allowed for the simulation of various rhVEGF(165) dose regimens that may aid in optimization of drug delivery for future clinical trials.

Adult↗
PubMed2002

Pathophysiology of coronary artery restenosis.

All forms of percutaneous coronary intervention confer injury on the vessel. The arterial response to that injury is the basis for long-term outcome. The stent prevents remodeling but enhances neointimal formation, and it is this neointima that is principally responsible for in-stent restenosis. Neointima forms in response to thrombus, inflammation, intimal and medial dissections, and elastic recoil of the arterial wall when a stent is not placed. Current efforts to solve restenosis center on limiting neointimal hyperplasia through drug-eluting stents and vascular brachytherapy. This article reviews arterial injury during revascularization in both patients and animal models and discusses the nature and formation of neointimal hyperplasia.

Angioplasty, Balloon↗