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Biomedical subjects

M Chiariello

Publications and source records attributed to M Chiariello.

At least 19 recordsLinked to original sources
PubMed2006

Neopterin induces pro-atherothrombotic phenotype in human coronary endothelial cells.

BACKGROUND: Inflammation plays a pivotal role in atherothrombosis. Recent data indicate that serum levels of neopterin, a marker of inflammation and immune modulator secreted by monocytes/macrophages, are elevated in patients with acute coronary syndromes and seem to be a prognostic marker for major cardiovascular events. The aim of the present study was to determine whether neopterin might affect the thrombotic and atherosclerotic characteristics of human coronary artery endothelial cells (HCAECs). METHODS AND RESULTS: In HCAECs, neopterin induced TF-mRNA transcription as demonstrated by real time polymerase chain reaction and expression of functionally active tissue factor (TF) as demonstrated by procoagulant activity assay, and of cellular adhesion molecules (CAMs) as demonstrated by FACS analysis, in a dose-dependent fashion. These neopterin effects were prevented by lovastatin, a HMG-CoA reductase inhibitor. Neopterin-induced TF and CAMs expression was mediated by oxygen free radicals through the activation of the transcription factor, nuclear factor-kappa B (NF-kappaB), as demonstrated by electrophoretic mobility shift assay and by suppression of CAMs and TF expression by superoxide dismutase and by NF-kappaB inhibitor, pyrrolidine-dithio-carbamate ammonium. CONCLUSIONS: These data indicate that neopterin exerts direct effects on HCAECs by promoting CAMs and TF expression and support the hypothesis that neopterin, besides representing a marker of inflammation, might be an effector molecule able to induce a pro-atherothrombotic phenotype in cells of the coronary circulation.

Cell Adhesion↗
PubMed2006

Nicotine induces tissue factor expression in cultured endothelial and smooth muscle cells.

BACKGROUND AND OBJECTIVES: Cigarette smoking is associated with an increased risk to develop myocardial infarction and ischemic stroke. However, the mechanisms responsible for these effects are still poorly understood. AIM: To investigate whether nicotine, the major component of cigarette smoking, and its main metabolite, cotinine, might induce a pro-thrombotic state via stimulation of tissue factor (TF) expression in two cell population widely represented in the arterial wall such as endothelial cells (ECs), and smooth muscle cells (SMCs). METHODS AND RESULTS: Incubation of ECs and SMCs with nicotine and cotinine induced TF expression in both cell types in a dose-dependent fashion, exerting its effect at the transcriptional level, as demonstrated by semiquantitative and by real-time PCR. Nicotine- and cotinine-induced TF expression was mediated by the activation of the transcription factor, nuclear factor-kappa B (NF-kappaB), as demonstrated by electrophoretic mobility shift assay and by the suppression of TF expression by the NF-kappaB inhibitor, pyrrolidine dithio carbamate ammonium. CONCLUSIONS: These data indicate that nicotine and cotinine exert direct effects on ECs and SMCs, shifting them toward a pro-thrombotic state via induction of TF expression. These effects on cells of the vessel wall might explain, at least in part, the deleterious cardiovascular consequences of cigarette smoking.

Animals↗
PubMed2005

Coronary stenting and abciximab in primary angioplasty for ST-segment-elevation myocardial infarction.

Advances in anti-platelet therapy and improvement of stent deployment techniques have improved the safety and efficacy of stenting in the setting of ST-segment-elevation myocardial infarction (STEMI). However, in randomized trials, routine coronary stenting does not reduce mortality and re-infarction, compared to balloon angioplasty. Further, the benefits in target vessel revascularization seem to be reduced when applied to unselected patients with STEMI. Direct stenting represents an attractive strategy with potential benefits in terms of myocardial perfusion. Future large randomized trials are needed to evaluate whether this strategy has a significant impact on outcome, and to provide a cost-benefit analysis of the unrestricted use of drug-eluting stents in this high-risk subset of patients. The additional use of abciximab reduces mortality in primary angioplasty. Since the feasibility of long-distance transportation has been shown in several randomized trials, early pharmacological pre-treatment may confer further advantages by early recanalization and shorter ischaemic time, particularly in high-risk patients. Further randomized trials are needed to clarify the potential benefits from early abciximab administration and the potential role of small molecules in primary angioplasty for STEMI.

Abciximab↗
PubMed2005

Late reopening of an occluded infarct related artery improves left ventricular function and long term clinical outcome.

OBJECTIVE: To assess effects on left ventricular (LV) function and on long term clinical outcome of late percutaneous transluminal coronary angioplasty (PTCA) of a chronically occluded infarct related artery. METHODS: 65 patients who underwent PTCA a mean (SD) of 6.0 (1.2) months after a previous myocardial infarction were divided in two groups according to dilated artery patency status after PTCA: group 1 (35 patients with TIMI (thrombolysis in myocardial infarction) grade 3 flow) and group 2 (30 patients with TIMI grade 0-2 flow). Echocardiography was performed at admission and at six months' follow up. A three year follow up was conducted with major adverse cardiac events (MACE) as end points. RESULTS: At follow up, group 1 had improved global LV ejection fraction (48.7% v 43.6%, p < 0.001) and LV indexed end diastolic and end systolic volumes (75 v 86 ml/m(2) and 40 v 53 ml/m(2), respectively, p = 0.011) compared with group 2. Kaplan-Meier analysis showed a higher incidence of cardiac death (p = 0.02) and MACE (p < 0.0001) in group 2. TIMI 3 after PTCA was an independent predictor of event-free survival at follow up. CONCLUSION: Late PTCA of a chronically occluded infarct related artery improves LV function, reduces cardiac death, and improves long term clinical outcome.

Angioplasty, Balloon, Coronary↗
PubMed2004

Sympathetic nervous function in patients with hypertrophic cardiomyopathy assessed by [123I]-MIBG: relationship with left ventricular perfusion and function.

AIM: The aim of the present study was to evaluate [123I] MIBG uptake and clearance in patients with hypertrophic cardiomyopathy (HCM) and to assess their relationships with left ventricular function (systolic and diastolic) and perfusion. METHODS: Eleven consecutive patients with HCM (8 men and 3 women; mean age 38+/-12 years, none in the dilated phase) underwent (in separate days, in random order) [123I]-MIBG scintigraphy, [(99m)Tc]-MIBI SPET at rest, and echocardiography. All patients were studied in fasting condition, and all medications were discontinued. [(99m)Tc]-MIBI SPET study was performed 1 hour after tracer injection. [123I]-MIBG study was acquired 5 minutes (planar) and 4 hours (planar and SPET) after the i.v. injection of [123I]-MIBG. Heart to mediastinum ratio (H/M) was computed at 4 hours. Wash out rate (WOR) was computed as: (H early - H delayed)/(H early), after decay correction. Both [123I]-MIBG and [(99m)Tc]-MIBI SPET were analyzed on 3 short axis views (apical, middle, and basal). Left ventricular outflow tract gradient (LVOTG), ejection fraction, volumes, septum thickness, and left atrial fractional shortening (LAFS) were evaluated on echocardiography. RESULTS: [123I]-MIBG WOR showed a positive relationship with LVOTG (r=0.84, p<0.001) and septum thickness (r=0.76, p<0.01), while a negative one was found with LAFS (r= -0.66, p<0.05). The study group was divided into: Group A (n=5) with higher, and Group B (n=6) with lower WOR than the median value (i.e. 11%). Group A patients had significantly lower LAFS (17.6+/-4.8 vs 26.8+/-7.2%, p<0.05), higher LVOTG (49+/-35 vs 3+/-3 mmHg), and thicker septum (21+/-2 vs 17+/-2 mm) than Group B patients. Inferior and septal wall [123I]-MIBG uptake on 4 hour SPET was significantly lower in Group A than in Group B. On the other hand, no differences were found in (99m)T-MIBI SPET rest regional uptake between the 2 subgroups of patients. CONCLUSION: These results suggest that cardiac sympathetic activity correlates to cardiac anatomy (i.e. degree of hypertrophy) and diastolic function in patients with HCM.

3-Iodobenzylguanidine↗
PubMed2003

Long-lasting antithrombotic effects of a single dose of human recombinant, active site-blocked factor VII: insights into possible mechanism(s) of action.

Tissue factor (TF) is important in initiating intravascular thrombosis. We demonstrated that active-site blocked factor VII (FVIIai) inhibits intravascular thrombosis for at least 6 h following a single injection, despite FVIIai plasma half-life was approximately 45 min. The aims of the present study were: (a) to determine the duration of the antithrombotic effects of a single injection of FVIIai; and (b) to assess whether FVIIai prolonged effects can be explained by a slow dissociation rate from TF in the arterial wall. Cyclic flow variations (CFVs), obtained in stenotic rabbit carotid arteries with endothelial injury, were abolished by either FVIIai (100 micro g kg-1 min-1 for 10 min) or hirudin (1 mg kg-1). After CFVs were abolished, carotid blood flow velocity was recorded continuously for 24 h. CFVs restored in all hirudin-treated animals after 2.1 +/- 0.3 h, while they restored in only four of nine FVIIai-treated rabbits in 10.1 +/- 2.2 h. Five animals in this group did not show restoration of CFVs up to 24 h. Immunohistochemistry revealed that FVIIai was still bound to the arterial wall 24 h following its administration, despite at this time FVIIai plasma levels were undetectable. Prothrombin time and partial thromboplastin time did not change significantly. FVIIai exerts potent, long-lasting antithrombotic effects without affecting systemic hemostatic parameters; a possible mechanism is a slow dissociation rate of FVIIai from TF. These proprieties make FVIIai particularly attractive as an antithrombotic intervention.

Animals↗
PubMed2001

Effects of balloon injury on neointimal hyperplasia in streptozotocin-induced diabetes and in hyperinsulinemic nondiabetic pancreatic islet-transplanted rats.

BACKGROUND: The mechanisms of increased neointimal hyperplasia after coronary interventions in diabetic patients are still unknown. METHODS AND RESULTS: Glucose and insulin effects on in vitro vascular smooth muscle cell (VSMC) proliferation and migration were assessed. The effect of balloon injury on neointimal hyperplasia was studied in streptozotocin-induced diabetic rats with or without adjunct insulin therapy. To study the effect of balloon injury in nondiabetic rats with hyperinsulinemia, pancreatic islets were transplanted under the kidney capsule in normal rats. Glucose did not increase VSMC proliferation and migration in vitro. In contrast, insulin induced a significant increase in VSMC proliferation and migration in cell cultures. Furthermore, in VSMC culture, insulin increased MAPK activation. A reduction in neointimal hyperplasia was consistently documented after vascular injury in hyperglycemic streptozotocin-induced diabetic rats. Insulin therapy significantly increased neointimal hyperplasia in these rats. This effect of hyperinsulinemia was totally abolished by transfection on the arterial wall of the N17H-ras-negative mutant gene. Finally, after experimental balloon angioplasty in hyperinsulinemic nondiabetic islet-transplanted rats, a significant increase in neointimal hyperplasia was observed. CONCLUSIONS: In rats with streptozotocin-induced diabetes, balloon injury was not associated with an increase in neointimal formation. Exogenous insulin administration in diabetic rats and islet transplantation in nondiabetic rats increased both blood insulin levels and neointimal hyperplasia after balloon injury. Hyperinsulinemia through activation of the ras/MAPK pathway, rather than hyperglycemia per se, seems to be of crucial importance in determining the exaggerated neointimal hyperplasia after balloon angioplasty in diabetic animals.

Angioplasty, Balloon↗
PubMed2001

Regulation of gene expression by the small GTPase Rho through the ERK6 (p38 gamma) MAP kinase pathway.

Small GTP-binding proteins of the Rho-family, Rho, Rac, and Cdc42, have been traditionally linked to the regulation of the cellular actin-based cytoskeleton. Rac and Cdc42 can also control the activity of JNK, thus acting in a molecular pathway transmitting extracellular signals to the nucleus. Interestingly, Rho can also regulate gene expression, albeit by a not fully understood mechanism. Here, we found that activated RhoA can stimulate c-jun expression and the activity of the c-jun promoter. As the complexity of the signaling pathways controlling the expression of c-jun has begun to be unraveled, this finding provided a unique opportunity to elucidate the biochemical routes whereby RhoA regulates nuclear events. We found that RhoA can initiate a linear kinase cascade leading to the activation of ERK6 (p38 gamma), a recently identified member of the p38 family of MAPKs. Furthermore, we present evidence that RhoA, PKN, MKK3/MKK6, and ERK6 (p38 gamma) are components of a novel signal transduction pathway involved in the regulation of gene expression and cellular transformation.

3T3 Cells↗
PubMed2001

Membrane-bound protein kinase A inhibits smooth muscle cell proliferation in vitro and in vivo by amplifying cAMP-protein kinase A signals.

cAMP-dependent protein kinase is anchored to discrete cellular compartments by a family of proteins, the A-kinase anchor proteins (AKAPs). We have investigated in vivo and in vitro the biological effects of the expression of a prototypic member of the family, AKAP75, on smooth muscle cells. In vitro expression of AKAP75 in smooth muscle cells stimulated cAMP-induced transcription, increased the levels of the cyclin-dependent kinase-2 inhibitor p27(kip1), and reduced cell proliferation. In vivo expression of exogenous AKAP75 in common carotid arteries, subjected to balloon injury, significantly increased the levels of p27(kip1) and inhibited neointimal hyperplasia. Both the effects in smooth muscle cells in vitro and in carotid arteries in vivo were specifically dependent on the amplification of cAMP-dependent protein kinase (PKA) signals by membrane-bound PKA, as indicated by selective loss of the AKAP75 biological effects in mutants defective in the PKA anchor domain or by suppression of AKAP effects by the PKA-specific protein kinase inhibitor. These data indicate that AKAP proteins selectively amplify cAMP-PKA signaling in vitro and in vivo and suggest a possible target for the inhibition of the neointimal hyperplasia after vascular injury.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed2001

Direct coronary stenting: effect on coronary blood flow, immediate and late clinical results.

Direct stenting (DS) was attempted in 99 coronary lesions in 94 patients while standard stenting (SS) was attempted in 113 lesions in 103 patients matched for clinical characteristics, stenosis type, and location and stent type. The angiographic result was also evaluated according to TIMI frame count method (TFC) before and after procedure. A clinical follow-up was performed 1 year after the procedure. Before the procedure, TIMI grade 3 flow was detected in 42 cases (42.4%), grade 2 in 40 cases (40.4%), grade 1 in 5 cases (5.1%), and grade 0 in 12 cases (12.1%) in the DS group; these data were similar in SS group. After the procedure, TIMI grade flow was 3 in 90 cases (92.8%) in DS group and in 87 (77.0%) in SS group (P < 0.005); grade 2 was observed in 7 case (7.2%) in DS group and in 25 (22.1%) in SS group (P < 0.005). Major adverse cardiac events during hospitalization and at follow-up were similar in two groups. Radiation exposure time and procedure costs per lesion were significantly reduced in DS group compared to SS group (10.1 +/- 8 min vs. 13.9 +/- 4.7 min, P < 0.001; and 1901 +/- 687 Euro vs. 2352 +/- 743 Euro, P < 0.001, respectively). This study confirms that, in selected patients, direct stenting is a safe and successful procedure, allowing a significant reduction in radiation exposure time and procedural costs compared to standard stenting technique. The angiographic success is confirmed by the improvement in TFC in all cases.

Abciximab↗
PubMed2001

Diagnostic accuracy of low-dose dobutamine echocardiography in predicting post-revascularisation recovery of function in patients with chronic coronary artery disease: relationship to thallium-201 uptake.

It is known that contractile reserve may be blunted if perfusion and coronary flow reserve are reduced. Thus, it is conceivable that the predictive accuracy of dobutamine echocardiography may differ according to perfusion tracer uptake. The aim of this study was therefore to assess the relationship between the level of thallium-201 uptake and the accuracy of dobutamine echocardiography in identifying reversible dysfunction. Sixty-nine patients (age 59+/-8 years, ejection fraction 40%+/-11%) with chronic coronary artery disease scheduled for coronary revascularisation were studied. All patients underwent rest 201Tl single-photon emission tomography and two-dimensional echocardiography at rest and during low-dose dobutamine infusion on the same day before revascularisation and repeated echocardiography at least 30 days thereafter. At follow-up, recovery of function was observed in 49% of 339 dysfunctional segments. The percentage of segments with post-revascularisation recovery of function and the percentage with contractile reserve increased in parallel with 201Tl uptake both in the total group of segments (chi2=35.5, P<0.0001 and chi2=35.9, P<0.0001, respectively) and among the 183 akinetic segments (chi2=44.4, P<0.0001 and chi2=14.6, P<0.05, respectively). The dysfunctional segments were divided into three groups according to 201Tl uptake: (a) uptake <65%, (b) uptake between 65% and 79%, (c) uptake >80%. The positive predictive value increased significantly with the level of 201Tl uptake, and was suboptimal (46%) in akinetic segments with severely reduced 201Tl uptake. The negative predictive value decreased significantly with 201Tl uptake, and it was less than suboptimal (29%) in akinetic segments with normal tracer uptake. Sensitivity was lower in the subset of akinetic segments (42%-63%) than in all dyssynergic segments (63%-76%), whereas specificity was very high in akinetic segments (80%-84%). It is concluded that the accuracy of low-dose dobutamine echocardiography in predicting reversibility of regional dysfunction varies considerably according to 201Tl uptake at rest and to the severity of regional dysfunction.

Adult↗
PubMed2001

Expression of exogenous tissue factor pathway inhibitor in vivo suppresses thrombus formation in injured rabbit carotid arteries.

OBJECTIVES: The aim of the present study was to test the hypothesis that retrovirus-mediated in vivo tissue factor pathway inhibitor (TFPI) gene transfer to the arterial wall would efficiently inhibit thrombosis without causing significant changes in systemic hemostatic variables. BACKGROUND: Acute coronary syndromes (unstable angina and acute myocardial infarction) are usually caused by atherosclerotic plaque rupture, with consequent activation of the coagulation cascade and circulating platelets. Tissue factor (TF) exposure represents an early event in this pathophysiologic sequence, leading to activation of the extrinsic coagulation pathway and thrombin formation. Tissue factor pathway inhibitor is a naturally occurring inhibitor of the extrinsic pathway. METHODS: In the present study, the gene coding for rabbit TFPI was inserted in a retroviral vector under control of a tetracycline-inducible promoter. Replication-defective, infectious, recombinant retroviruses were used to transfect rabbit carotid arteries with either TFPI or a reporter gene--green fluorescent protein (GFP). RESULTS: Retroviral-mediated arterial gene transfer of TFPI resulted in potent inhibition of intravascular thrombus formation in stenotic and injured rabbit carotid arteries, whereas transfection of the contralateral carotid artery with GFP had no effect on thrombosis. No significant changes in systemic hemostatic variables (prothrombin time and partial thromboplastin time) were observed when thrombosis was inhibited. CONCLUSIONS: These data suggest that retroviral-mediated transfection of the arterial wall with TFPI might represent an attractive approach for the treatment of thrombotic disorders.

Animals↗
PubMed2001

Regulation of c-myc expression by PDGF through Rho GTPases.

Src family protein-tyrosine kinases have a central role in several biological functions, including cell adhesion and spreading, chemotaxis, cell cycle progression, differentiation and apoptosis. Surprisingly, these kinases also participate in mitogenic signalling by receptors that themselves exhibit an intrinsic protein-tyrosine kinase activity, including those for platelet-derived growth factor (PDGF), epidermal growth factor and colony-stimulating factor-1. Indeed, Src kinases are strictly required for the nuclear expression of the c-myc proto-oncogene and thus for DNA synthesis in response to PDGF. However, the nature of the signalling pathways by which Src kinases participate in the induction of c-myc expression by tyrosine kinase receptors is still unknown. Here we show that PDGF enhances c-myc expression and stimulates the c-myc promoter in a Src-dependent manner, and that neither Ras nor the mitogen-activated protein kinase pathway mediate these effects. In contrast, we present evidence that PDGF stimulates Vav2 through Src, thereby initiating the activation of a Rac-dependent pathway that controls the expression of the c-myc proto-oncogene.

3T3 Cells↗
PubMed2001

Determinants and clinical significance of natriuretic peptides and hypertrophic cardiomyopathy.

AIMS: Atrial and brain natriuretic peptide levels closely reflect impaired left ventricular function in patients with heart failure. In the present study we assessed the determinants and the clinical significance of atrial and brain natriuretic peptide plasma levels in hypertrophic cardiomyopathy. METHODS AND RESULTS: In 44 patients with hypertrophic cardiomyopathy (40+/-15 years) we evaluated: (a) atrial and brain natriuretic peptide plasma levels; (b) left ventricular hypertrophy; (c) left ventricular ejection fraction; (d) transmitral and pulmonary venous flow velocity patterns, and left atrial fractional shortening; (e) left ventricular outflow tract gradient; (f) maximal oxygen consumption. Left ventricular hypertrophy influenced only brain natriuretic peptide levels (r=0.32;P<0.05). Atrial and brain natriuretic peptide plasma levels did not correlate with left ventricular ejection fraction, but correlated with left ventricular outflow tract gradient (r=0.35;P<0.05; and r=0.40, P=0.022, respectively) and left atrial fractional shortening (r=-0.57;P<0.001, and r=-0.35;P<0.05, respectively). Atrial but not brain natriuretic peptide plasma levels were inversely related to maximal oxygen consumption (r=-0.35;P<0.05). By stepwise multiple regression analysis, left atrial fractional shortening and left ventricular outflow tract gradient were the only predictors of atrial and brain natriuretic peptide plasma levels, respectively. CONCLUSIONS: In hypertrophic cardiomyopathy, atrial natriuretic peptide plasma levels are mainly determined by diastolic function: this explains the relationship with exercise tolerance. In contrast, brain natriuretic peptide plasma levels are mainly determined by left ventricular outflow tract gradient.

Adolescent↗
PubMed2001

Low dose dobutamine echocardiography for predicting functional recovery after coronary revascularisation.

OBJECTIVE: To evaluate the effects of chronic coronary occlusion on the accuracy of low dose dobutamine echocardiography in predicting recovery of dysfunctional myocardium after revascularisation. DESIGN: Retrospective study. SETTING: Tertiary referral centre. PATIENTS: 53 consecutive patients with >/= 70% stenosis of the left anterior descending coronary artery (LAD) and regional ventricular dysfunction (group 1, non-occluded LAD; group 2, occluded LAD) who underwent dobutamine echocardiography. INTERVENTIONS: 26 patients underwent coronary artery bypass grafting and 27 had percutaneous transluminal coronary angioplasty. MAIN OUTCOME MEASURES: Baseline studies before revascularisation included cross sectional echocardiography at rest and during dobutamine infusion (5-10 microgram), and coronary angiography. The dobutamine study was performed mean (SD) 35 (28) days before revascularisation. Echocardiography at rest was repeated 90 (48) days after revascularisation. RESULTS: Of 296 dysfunctional segments, 63 in group 1 (43%; 63/146) and 69 in group 2 (46%; 69/150) (NS) improved at follow up. Mean (SD) regional wall motion score index decreased from 1.97 (0.48) (95% confidence interval (CI) 1.01 to 2.93) before revascularisation to 1.74 (0.52) (95% CI 0.70 to 2.78) at follow up in group 1 (p = 0.001), and from 2.12 (0.41) (95% CI 1.30 to 2.98) to 1.88 (0.36) (95% CI 1.16 to 2.60) in group 2 (p = 0.0006). In group 1, sensitivity (87% v 52%; p < 0.0001), negative predictive value (88% v 65%; p = 0.001), and accuracy (77% v 64%; p = 0.01) were all significantly higher than in group 2, despite the angiographic evidence of collaterals in patients with occluded vessels. CONCLUSIONS: Dobutamine echocardiography shows reduced sensitivity in predicting recovery of dysfunctional myocardium supplied by totally occluded vessels. Thus caution should be used in selecting such patients for revascularisation on the basis of a viability assessment made in this way.

Angioplasty, Balloon, Coronary↗