Search PubMed⌕ Search

Biomedical subjects

David C Sane

Publications and source records attributed to David C Sane.

52 records · Page 3Linked to original sources
PubMed2003

Effects of clopidogrel and aspirin combination versus aspirin alone on platelet aggregation and major receptor expression in patients with heart failure: the Plavix Use for Treatment Of Congestive Heart Failure (PLUTO-CHF) trial.

BACKGROUND: Persistent platelet activation may contribute to thrombotic events in patients with congestive heart failure (CHF). Chronic use of mild platelet inhibitors could therefore represent an independent avenue to improve morbidity, mortality, and quality of life in this expanding population. Although clopidogrel is widely used in patients with acute coronary syndromes and ischemic stroke, the ability of this novel ADP-receptor antagonist to inhibit platelet function in patients with CHF is unknown. We assessed antiplatelet properties of clopidogrel with aspirin (C+A) versus aspirin alone (A) in patients with CHF with heightened platelet activity. METHODS: Patients with left ventricular ejection fraction <40%, or CHF symptoms in the setting of preserved systolic function and New York Heart Association class II-IV were screened. Patients were considered to have platelet activation when 4 of the following 5 parameters were met: ADP-induced platelet aggregation >60%; collagen-induced aggregation >70%; whole blood aggregation >18 ohms; expression of GP IIb/IIIa >220 log MFI; and P-selectin cell positivity >8%. All patients were treated with 325 mg of acetylsalycilic acid (ASA) for at least 1 month. Patients receiving an antithrombotic agent other than ASA were excluded. Patients meeting clinical and laboratory criteria were randomly assigned to C+A (n=25), A (n=25) groups, or represent screen failures (n=38). Platelet studies (conventional and whole blood aggregometry, shear-induced activation, expression of 10 major receptors and formation of platelet-leukocyte microparticles) were performed at baseline and after 30 days of therapy. RESULTS: There were no deaths, hospitalizations, or serious adverse events. There were no changes in platelet parameters in the A group. In contrast, therapy with C+A resulted in a significant inhibition of platelet activity assessed by ADP-induced (P =.00001), and epinephrine-induced (P =.0016) aggregation, closure time (P =.04), expression of PECAM-1 (P =.009), GP Ib (P =.006), GP IIb/IIIa antigen (P =.0001), GP IIb/IIIa activity with PAC-1 (P =.0021), and CD151 (P =.0026) when compared with the A group. Therapy with C+A also resulted in the reduced formation of platelet-leukocyte microparticles (P =.021). Collagen-induced aggregation in plasma and in whole blood, expression of vitronectin receptor, P-selectin, CD63, CD107a, and CD107b did not differ among groups. CONCLUSIONS: Treatment with C+A for 1 month provides significantly greater inhibition of platelet activity than ASA alone in patients with CHF. Patients with CHF with heightened platelet activity represent a potential target population in which addition of clopidogrel may decrease mortality rates by reducing the incidence of thrombotic vascular events.

Aged↗
PubMed2003

Bicuspid aortic valves in monozygotic twins.

Identical bicuspid valve anomalies were found in monozygotic twins. Screening echocardiography should be considered for first-degree relatives of patients with bicuspid aortic valve.

Adult↗
PubMed2003

No effect of an L-arginine-enriched medical food (HeartBars) on endothelial function and platelet aggregation in subjects with hypercholesterolemia.

BACKGROUND: Providing L-arginine as a precursor for nitric oxide has been proposed to improve endothelial function in populations at high risk for cardiovascular events. We studied the effects of dietary L-arginine supplementation with HeartBars (a medical food rich in L-arginine, Cooke Pharma, Belmont, Calif) on flow-mediated dilation and markers of endothelial function in subjects with hypercholesterolemia. METHODS: We randomly assigned 47 subjects with hypercholesterolemia to receive one HeartBar containing 3.3 g L-arginine each, or a placebo bar, consumed twice daily for 2 weeks. Flow-mediated dilation, platelet aggregation studies, and soluble levels of endothelial and platelet adhesion molecules were obtained before and after the 2-week treatment period. RESULTS: Baseline and follow-up levels of L-arginine were 78.5 +/- 28.2 micromol/L and 80.7 +/- 26.7 micromol/L, respectively (P =.54). The HeartBar group had no improvement in flow-mediated dilation; changes in brachial artery diameter at baseline and follow-up were 5.52% +/- 3.32% and 4.96% +/- 2.39%, respectively. There were also no changes in the soluble levels of E-selectin and P-selectin by treatment group. CONCLUSIONS: In our study, 2 weeks of HeartBar supplementation in subjects with hypercholesterolemia showed no favorable effects on endothelial or platelet function.

Ambulatory Care↗
PubMed2003

Platelet activation in patients with congestive heart failure: do we have enough evidence to consider clopidogrel?

Our understanding of the pathogenesis of congestive heart failure (CHF) has improved remarkably in recent years. However, despite better knowledge and novel pharmaceutical strategies, this disease is still one of the most brutal killers in the Western world. The pathophysiology of CHF is complex, and much of our comprehension revolves strictly around the neurohormonal and mechanical mechanisms involved. It has been suggested that CHF is associated with altered hemostasis, but whether a prothrombotic state contributes to the pathogenesis and progression of the disease is still not well known. The purpose of this review article is to discuss our current knowledge of platelet activation in patients with CHF and the potential role of antiplatelet agents in preventing these hemostatic abnormalities. Clopidogrel is an established medication that reduces the incidence of stroke, myocardial ischemia, or vascular death. It is currently the drug of choice in the prophylaxis of subacute stent thrombosis and postischemic stroke treatment. Promising results of the most resent trials (Clopidogrel versus Aspirin in Patients at Risk of Ischemic Events [CAPRIE] and Clopidogrel in Unstable angina to prevent Recurrent Events [CURE]) may expand future indications of this ADP receptor antagonist for prevention of thrombotic complications in the CHF population. Currently conducted clinical trials (Warfarin and Antiplatelet Therapy in Chronic Heart Failure [WATCH] and Plavix Use for Treatment of Congestive Heart Failure [PLUTO-CHF] should clarify the role of clopidogrel in these patients.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2003

Enhanced platelet/endothelial activation in depressed patients with acute coronary syndromes: evidence from recent clinical trials.

Platelets play a key role in the progression of acute coronary syndromes (ACS). Clinical depression alone is also associated with enhanced platelet activation. The purpose of this study was to compare concentrations of established biomarkers of enhanced platelet/endothelial activation in clinically depressed versus non-depressed patients enrolled in recent clinical trials for ACS. Two hundred and eighty-one baseline plasma samples from patients with acute myocardial infarction (ASSENT-2; n = 41), with ACS (PRONTO; n = 126) and with clinical depression plus previous acute coronary syndrome within 6 months (SADHART; n = 64), and from normal healthy controls (n = 50) were analyzed. Blood was drawn before applying any therapeutic strategies including interventions, thrombolytics, infusions, and selective serotonin re-uptake inhibitors. Platelet factor 4, beta-thromboglobulin, platelet/endothelial cell adhesion molecule-1, P-selectin, thromboxane, prostacyclin, vascular cell adhesion molecule-1, and E-selectin were measured by enzyme-linked immunosorbent assay by a single core laboratory. Patients with ACS exhibited a higher degree of platelet activation than controls independently of the presence of depression. Plasma levels of P-selectin, thromboxane, prostacyclin, and vascular cell adhesion molecule-1 were the highest in the acute myocardial infarction group when compared with ACS despite the presence or absence of clinical depression. Surprisingly, patients with ACS and depression exhibited the highest levels of platelet factor 4, beta-thromboglobulin, and platelet/endothelial cell adhesion molecule-1 when compared with myocardial infarction or angina patients without clinical depression. E-selectin plasma level was constantly elevated compared with controls but did not differ among the groups dependent on the incidence of depression. The depressed plus ACS group had higher plasma levels of all biomarkers compared with the non-depressed patients. Retrospective analysis of the data from several clinical trials reveals that clinical depression is associated with enhanced activation of platelet/endothelial biomarkers even above the level expected in ACS. These findings may contribute to the unfavorable outcome associated with clinical depression in patients with ACS.

Acute Disease↗
PubMed2002

Vitamin K 2,3-epoxide reductase and the vitamin K-dependent gamma-carboxylation system.

Vitamin K is an essential cofactor for post translational gamma-carboxylation of vitamin K-dependent coagulation factors. The modification is carried out by a system of integral proteins of the endoplasmic reticulum (ER) membrane where the warfarin sensitive vitamin K 2,3-epoxide reductase (VKOR) produces the reduced hydroquinone form of vitamin K (vit.KH(2)) needed by the gamma-carboxylase as the active cofactor. Currently, we have only limited knowledge about how the system functions at the molecular level. VKOR harbors a thiol red/ox center that is essential for electron transfer leading to vitamin K reduction. Reduction of this center with hydrophilic and hydrophobic trialkylphosphines shows that it is located in a hydrophobic environment which must be accessible by an as yet unidentified in vivo reductant of the center. Furthermore, we have addressed the question of whether VKOR or the gamma-carboxylase is the rate-limiting step in the vitamin K-dependent gamma-caboxylation system. A detailed kinetic analysis of an in vitro preparation of the system was undertaken in which gamma-carboxylation of the carboxylase peptide substrate FLEEL was measured as the gamma-carboxylation capacity of the system. Adding VKOR to the test system increased the gamma-carboxylation capacity of the system suggesting that VKOR is the rate-limiting step in the system. This finding puts VKOR in a central position to regulate biosynthesis of biologically active vitamin K-dependent proteins.

Animals↗
PubMed2002

Angiostatin selectively inhibits signaling by hepatocyte growth factor in endothelial and smooth muscle cells.

Angiostatin, an inhibitor of angiogenesis, contains 3 to 4 kringle domains that are derived from proteolytic cleavage of plasminogen. The antiangiogenic effects of angiostatin occur, in part, from its inhibition of endothelial cell surface adenosine triphosphate synthase, integrin functions, and pericellular proteolysis. Angiostatin has structural similarities to hepatocyte growth factor (HGF; "scatter factor"), a promoter of angiogenesis, that induces proliferation and migration of both endothelial and smooth muscle cells via its cell surface receptor, c-met. We hypothesized that angiostatin might block HGF-induced signaling in endothelial and smooth muscle cells. Angiostatin inhibited HGF-induced phosphorylation of c-met, Akt, and ERK1/2. Angiostatin also significantly inhibited proliferation of human umbilical vein endothelial cells (HUVECs) induced by HGF. In contrast, angiostatin did not inhibit vascular endothelial growth factor (VEGF)-or basic fibroblast growth factor (bFGF)-induced signaling events or HUVEC proliferation. Angiostatin bound to immobilized truncated c-met produced by A431 cells and could be immunoprecipitated as a complex with soluble c-met. HGF inhibited the binding of (125)I-angiostatin to HUVECs. Soluble c-met, produced by several tumor cell lines, could inhibit the antiangiogenic effect of angiostatin. The disruption of HGF/c-met signaling is a novel mechanism for the antiangiogenic effect of angiostatin.

Angiostatins↗
PubMed2002

Vascular origin of a soluble truncated form of the hepatocyte growth factor receptor (c-met).

Hepatocyte growth factor (scatter factor) is an angiogenic growth factor that binds to its cellular transmembrane receptor, c-met. Both HGF and c-met are expressed by vascular smooth muscle and endothelial cells, where HGF may exert autocrine and paracrine effects. We have found that human aortic smooth muscle cells (HASMCs) and human umbilical vein endothelial cells (HUVECs) release a soluble, truncated form of c-met. Receptor shedding was induced by treatment of the cells with phorbol 12-myristate 13-acetate (PMA) and by the ligand, HGF. Shedding was inhibited by cycloheximide, a metalloproteinase inhibitor, and protein kinase C inhibitors. The soluble form of c-met was able to bind HGF, although with reduced affinity (K(d) approximately 10 nmol/L) compared with the membrane bound receptor. Conditioned medium containing soluble c-met inhibited the induction of Akt phosphorylation by HGF in HUVECs. The soluble truncated form of c-met was detectable in the plasma of 5 healthy volunteers. The shedding of c-met may represent a novel mechanism for regulating the mitogenic, motogenic, and morphogenic effects of hepatocyte growth factor.

Cell Line↗
PubMed2002

Growth hormone, insulin-like growth factor-1 and the aging cardiovascular system.

There is a large body of evidence that biological aging is related to a series of long-term catabolic processes resulting in decreased function and structural integrity of several physiological systems, among which is the cardiovascular system. These changes in the aging phenotype are correlated with a decline in the amplitude of pulsatile growth hormone secretion and the resulting decrease in plasma levels of its anabolic mediator, insulin like growth factor-1 (IGF-1). The relationship between growth hormone and biological aging is supported by studies demonstrating that growth hormone administration to old animals and humans raises plasma IGF-1 and results in increases in skeletal muscle and lean body mass, a decrease in adiposity, increased immune function, improvements in learning and memory, and increases in cardiovascular function. Since growth hormone and IGF-1 exert potent effects on the heart and vasculature, the relationship between age-related changes in cardiovascular function and the decline in growth hormone levels with age have become of interest. Among the age-related changes in the cardiovascular system are decreases in myocyte number, accumulation of fibrosis and collagen, decreases in stress-induced cardiac function through deterioration of the myocardial conduction system and beta-adrenergic receptor function, decreases in exercise capacity, vessel rarefaction, decreased arterial compliance and endothelial dysfunction leading to alterations in blood flow. Growth hormone has been found to exert potent effects on cardiovascular function in young animals and reverses many of the deficits in cardiovascular function in aged animals and humans. Nevertheless, it has been difficult to separate the effects of growth hormone deficiency from age-related diseases and associated pathologies. The development of novel animal models and additional research are required in order to elucidate the specific effects of growth hormone deficiency and assess its contribution to cardiovascular impairments and biological aging.

Aged↗
PubMed2002

Aging and thrombosis.

Advanced age is associated with a dramatic increase in the rates of venous and arterial thrombotic events. Increases in fibrinogen, factors VIII and IX, and other coagulation proteins, without a proportional increase in anticoagulant factors, likely contribute to this risk. Recent studies have delineated a role for genomic elements in controlling age-related expression of some coagulation proteins. Enhanced platelet activity as well as molecular and anatomic changes in the vessel wall also contribute to the thrombotic propensity. Advanced age is associated with elevated interleukin-6 (IL-6) and C-reactive protein levels, indicating an inflammatory state that may be an important stimulus for thrombus formation in the elderly. Despite evidence of a prothrombotic state, many elderly people do not experience clinical thrombotic events. It is possible that the increase in coagulation proteins and activation markers conveys a survival advantage, such as inhibiting tumor angiogenesis. The recent epidemic in obesity may heighten thrombotic risks in the elderly because adipose tissue is an important source of inflammatory cytokines and plasminogen activator inhibitor-1 (PAI-1). As the population ages, further studies will be warranted to define the mechanisms for thrombosis in the elderly.

Aged↗
PubMed2002

Reduced inhibition by abciximab in platelets with the PlA2 polymorphism.

BACKGROUND: The PlA2 polymorphism of the glycoprotein IIb/IIIa (fibrinogen) receptor has been associated with increased restenosis and stent thrombosis. We postulated that this allele could alter the antiplatelet effect of abciximab in patients undergoing percutaneous coronary intervention. METHODS: Optical platelet aggregation assays, Ultegra (Accumetrics, San Diego) rapid platelet function assays, and radiometric abciximab binding assays were performed in 66 Pl(A1/A1) and 21 PlA1/A2 patients undergoing percutaneous coronary interventions. The affinity of abciximab for the PlA1 and PlA2 receptors was determined with use of transfected cells. RESULTS: Compared with PlA1/A1 homozygotes, PlA1/A2 platelets were less completely inhibited after abciximab bolus (P =.002) and at 24 hours (P =.02) as assessed by the rapid platelet function assays. Optical aggregation assays confirmed that Pl(A1/A2) platelets were less completely inhibited after abciximab bolus (P =.05). The radiometric abciximab binding assay demonstrated that the PlA1/A2 platelets had fewer baseline fibrinogen receptors than did the PlA1/A1 platelets (P =.04) and more free fibrinogen receptors at 24 hours (P =.008). Cells transfected to express homozygous PlA1 or PlA2 demonstrated a nonsignificant trend (P =.12) for reduced abciximab affinity for PlA2. CONCLUSIONS: PlA1/A2 platelets are less completely inhibited with abciximab, contributing to the observed interindividual variability in platelet function inhibition. Because the extent of platelet inhibition is an independent predictor for the risk of major adverse coronary events after percutaneous coronary intervention, the relative resistance of PlA2-positive platelets may contribute to a less favorable outcome in these patients.

Abciximab↗
PubMed2002

The Ultegra rapid platelet-function assay: comparison to standard platelet function assays in patients undergoing percutaneous coronary intervention with abciximab therapy.

BACKGROUND: Despite the proven benefit of glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention, significant interpatient variability exists in antiplatelet response. Furthermore, a diminished degree of platelet inhibition is an independent predictor of adverse cardiac events, highlighting the need for accurate and precise monitoring of platelet function. METHODS: Patients (n = 192) who underwent elective percutaneous coronary intervention at 4 centers were enrolled. The following 3 time points were studied: 1, baseline, before abciximab bolus administration; 2, during, within 1 hour of abciximab bolus administration; and 3, post, 24 hours after abciximab bolus administration or at the time of patient discharge, whichever occurred first. The following 3 assays were compared at all time points: Ultegra rapid platelet-function assay (Ultegra RPFA), conventional turbidometric platelet aggregometry, and receptor binding assay with [125I]-abciximab. Variability in Ultegra RPFA measurements between operators was determined with performance of the assays at the point of care and in the laboratory. A sub-study of 22 patients at 1 center was performed in which the laboratory scientist performed all 3 assays in duplicate at each time point. RESULTS: Comparison with the receptor binding assay and conventional platelet aggregometry in 120 patients showed that the Ultegra RPFA correlated with aggregometry (r = 0.89) and with the receptor binding assay (r = 0.89). There was good agreement (r = 0.80) between values obtained by intended users and those obtained by laboratory scientists. Furthermore, Ultegra RPFA values had equivalent precision to the standard assays. CONCLUSION: The Ultegra RPFA has equivalent accuracy and precision when compared with the 2 reference assays studied. Ultegra RPFA measurements are not operator-dependent and are not influenced by concomitant medications, hematologic parameters, or demographics.

Abciximab↗