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Biomedical subjects

M Chiariello

Publications and source records attributed to M Chiariello.

At least 145 records · Page 8Linked to original sources
PubMed1995

Aurintricarboxylic acid reduces platelet deposition in stenosed and endothelially injured rabbit carotid arteries more effectively than other antiplatelet interventions.

In the present study we tested the effects of different antithrombotic interventions on platelet deposition in experimentally-stenotic rabbit carotid arteries with endothelial injury. Platelet deposition, quantitated by labeling autologous platelets with 111In-oxine, was significantly reduced compared to control animals by all interventions tested, i.e., R 68070, a drug with thromboxane A2 synthase and receptor blocking properties, BN 52021, a PAF receptor antagonist, aurintricarboxylic acid (ATA), an inhibitor of platelet glycoprotein (Gp) Ib/von Willebrand factor (vWf) interaction, AZ-1, a monoclonal antibody against rabbit GP IIb/IIIa, the platelet receptor for fibrinogen, and AP-1, a monoclonal antibody against rabbit tissue factor. ATA was significantly more effective than all the other interventions in reducing platelet deposition in the stenotic vessels. We conclude that inhibition of Gp Ib/vWf interaction may be a more suitable target for antithrombotic therapy under conditions of high shear stress, like those produced in this model.

Analysis of Variance↗
PubMed1994

Rab5a is a common component of the apical and basolateral endocytic machinery in polarized epithelial cells.

In nonpolarized cells, the small GTPase Rab5a is localized to the plasma membrane, clathrin-coated vesicles, and early endosomes. Rab5a is required for early endosome fusion in vitro and regulates transport between the plasma membrane and early endosomes, in vivo. In polarized epithelial cells endocytosis occurs from separate apical and basolateral plasma membrane domains. Internalized molecules are initially delivered to distinct apical or basolateral early endosomes. In vitro, apical early endosomes can readily fuse with one another but not with the basolateral endosomes and vice versa, thereby indicating that the apical and basolateral early endocytic pathways are controlled by distinct machineries. Here, we have investigated the localization and function of Rab5a in polarized epithelial cells. Confocal immunofluorescence microscopy on mouse kidney sections revealed association of the protein with the apical and basolateral plasma membrane domains and underlying structures. In polarized Madin-Darby canine kidney I cells, endogenous and overexpressed Rab5a have the same distribution. Moreover, overexpression of the protein causes a 2-fold increase in fluid-phase uptake from both domains of the cell, thus showing that Rab5a functions in apical and basolateral endocytosis. Our data indicate that the apical and basolateral endocytic machineries of epithelial cells share common regulatory components and that Rab5a per se is not sufficient to target endocytic vesicles to apical or basolateral early endosomes.

Amino Acid Sequence↗
PubMed1994

Local effect of serotonin released during coronary angioplasty.

BACKGROUND: Serotonin is released after the aggregation of platelets, a phenomenon that may occur after coronary angioplasty. We sought to determine whether serotonin is released into the coronary circulation during coronary angioplasty and to assess whether serotonin can affect coronary-artery tone during angioplasty. METHODS: Blood samples were drawn from the ascending aorta and the coronary sinus of eight patients scheduled to undergo angioplasty of the left anterior descending or circumflex coronary artery. Samples were obtained before angioplasty and after each balloon dilation. The dimensions of arterial segments distal to the site of dilation were measured angiographically before angioplasty and 5 and 15 minutes after the last dilation in these eight patients and in seven similar patients; the latter group was treated with ketanserin, a serotonin2-receptor antagonist, before angioplasty. RESULTS: Before the eight patients underwent angioplasty, their mean (+/- SE) plasma serotonin level in the aorta was 2.5 +/- 0.7 ng per milliliter and that in the coronary sinus was 2.3 +/- 0.6 ng per milliliter (P = 0.34). The serotonin level in plasma from the coronary sinus rose significantly, to 31.5 +/- 13.5, 17.6 +/- 5.3, and 29.1 +/- 8.1 ng per milliliter after the first, second, and third dilations, respectively (P = 0.014 for the comparison with preoperative levels). In contrast, the serotonin level in plasma from the ascending aorta did not change. The cross-sectional area of the coronary artery was significantly reduced 5 and 15 minutes after the last dilation (from a preoperative value of 3.7 +/- 0.5 mm2 to 2.7 +/- 0.4 mm2 15 minutes after the last dilation; P = 0.011). This vasoconstriction was significantly blunted in the seven patients who received ketanserin (from 3.7 +/- 0.5 mm2 before angioplasty to 3.9 +/- 0.4 mm2 after 15 minutes) (P = 0.017 for comparison with the eight patients who did not receive ketanserin). CONCLUSIONS: Serotonin is released into the coronary circulation during angioplasty, and this vasoactive substance may contribute to the occurrence of vasoconstriction distal to the dilated site. The vasoconstriction is attenuated by ketanserin, a serotonin2-receptor antagonist.

Angioplasty, Balloon, Coronary↗
PubMed1994

Coronary artery vasoconstriction after successful single angioplasty of the left anterior descending artery.

Percutaneous transluminal coronary angioplasty is associated with spontaneous transient vasoconstriction. The mechanisms by which coronary vasoconstriction occurs distally to a successful dilated stenosis after coronary artery angioplasty are still unknown. The present study was planned to investigate the effect of successful coronary artery angioplasty on coronary vasomotion distal to a dilated stenosis and in the control vessel and the role of alpha-adrenergic receptors on coronary vasomotion after successful coronary artery angioplasty. We prospectively studied 32 consecutive patients scheduled for elective single coronary artery angioplasty of the left anterior descending coronary artery. Only aspirin, 325 mg, or nitroglycerin was allowed in the week before the study; no premedication with diazepam or other drugs was given. In group 1 (control patients, n = 20), quantitative coronary angiography was performed in the control state; 5 and 15 minutes after coronary artery angioplasty; and after intracoronary nitroglycerin infusion, 300 micrograms. In group 2 (n = 12), intracoronary phentolamine, 2 mg, was infused regionally through the balloon catheter before the coronary artery angioplasty, and coronary angiography was performed at baseline, 15 minutes after balloon deflation, and after nitroglycerin infusion. In group 1, constriction of the coronary segment distal to a dilated stenosis (2.4 +/- 0.8 to 2.1 +/- 0.6 mm, -14.6% vs baseline; p < 0.05) and of the circumflex coronary artery segment (2.8 +/- 0.7 to 2.5 +/- 0.6 mm, -10.7% vs baseline, p < 0.05) occurred 15 minutes after coronary artery angioplasty. The degree of vasoconstriction was not correlated with the lesion severity before coronary artery angioplasty.(ABSTRACT TRUNCATED AT 250 WORDS)

Angioplasty, Balloon, Coronary↗
PubMed1994

Influence of reversible segmental left ventricular dysfunction on heart period variability in patients with one-vessel coronary artery disease.

OBJECTIVES: This study evaluated the relation between reversible segmental left ventricular dysfunction and frequency domain measures of heart period variability in patients with coronary artery disease. BACKGROUND: Heart period variability is frequently reduced in patients with coronary artery disease. However, the mechanisms of this reduction are still unclear. METHODS: Echocardiographic left ventricular wall motion and frequency domain measures of heart period variability were evaluated in 32 patients with one-vessel coronary artery disease before and 16 to 24 days after successful percutaneous transluminal coronary angioplasty. Of these, 12 patients (Group A) had normal and 20 patients (Group B) had abnormal regional wall motion. A control group of 15 healthy subjects (Group C) underwent 24-h Holter recording twice at 2-week intervals to check for spontaneous variations. RESULTS: At baseline, low and high frequency power were lower in Group B than in Groups A and C, whereas no difference was detectable in ultra low and very low frequency and total power. After coronary angioplasty, regional wall motion and frequency domain measures of heart period variability were unchanged in Group A. In Group B the mean (+/- SD) summed segment score improved from 17.1 +/- 3.6 to 12.8 +/- 2.0 (p < 0.01), and mean low and high frequency power (logarithmic units) increased from 6.14 +/- 0.23 to 6.35 +/- 0.34 (p < 0.01) and from 5.43 +/- 0.32 to 5.68 +/- 0.52 (p < 0.01), respectively. Furthermore, low and high frequency power, lower at baseline in Group B than in the other two groups, were comparable in the three groups after coronary angioplasty. CONCLUSIONS: This study demonstrates that segmental left ventricular dysfunction is involved in determining sympathovagal imbalance in patients with one-vessel coronary artery disease; the reversal of left ventricular dysfunction by successful coronary angioplasty improves the heart period power spectrum. Thus, alterations in cardiac geometry influence the discharge of afferent sympathetic mechanoreceptors, contributing to the derangement in autonomic control of heart rate.

Afferent Pathways↗
PubMed1994

IPO-V2: a prospective, multicenter, randomized, comparative clinical investigation of the effects of sulodexide in preventing cardiovascular accidents in the first year after acute myocardial infarction.

OBJECTIVES: This study was conducted to assess the efficacy of sulodexide, a glycosaminoglycan compound with antithrombotic properties, in preventing death and thromboembolic events after acute myocardial infarction. BACKGROUND: Antithrombotic therapy has been found to play an important role in the prevention of cardiovascular events and death after acute myocardial infarction. Glycosaminoglycan-containing compounds, including sulodexide, show profibrinolytic and antithrombotic properties that render them suitable for use in patients after infarction. METHODS: A total of 3,986 patients who had recovered from acute myocardial infarction were randomized to receive either the standard therapy routinely administered at each study center, excluding antiplatelet and anticoagulant drugs (control group, 1,970 patients), or the standard therapy plus sulodexide (treated group, 2,016 patients). Between 7 and 10 days after the episode of acute myocardial infarction, sulodexide was administered as a single daily 600-lipoprotein-lipase-releasing unit (LRU) intramuscular injection for the 1st month, followed by oral capsules of 500 LRU twice daily. Patients were evaluated for > or = 12 months. RESULTS: At the end of the study, 140 deaths (7.1%) were recorded in the control group and 97 (4.8%) in the sulodexide group (32% risk reduction, p = 0.0022, chi-square test). A total of 90 patients (4.6%) in the control group had a further infarction, compared with 66 (3.3%) in the sulodexide group (28% risk reduction, p = 0.035). Furthermore, a reduction in left ventricular thrombus formation (evaluated by echocardiography) was observed in the sulodexide group (n = 12; 0.6%), compared with values in the control group (n = 25; 1.3%) (53% risk reduction, p = 0.027). Sulodexide was well tolerated and devoid of significant adverse events. All significant results were confirmed by "actual treatment" analyses. CONCLUSIONS: The study provides evidence that long-term therapy with sulodexide started early after an episode of acute myocardial infarction is associated with reductions in total mortality, rate of reinfarction and mural thrombus formation.

Aged↗
PubMed1994

Assessment of left ventricular regional function by radionuclide angiography: effects of number of sectors on repeatability.

Twenty patients were studied by equilibrium radionuclide angiography (RNA) twice in the same day in order to assess the repeatability of quantitative measurements of left ventricular (LV) regional function by using a sector analysis method. RNA was performed in the best septal 45 degrees left anterior oblique projection, acquiring 150,000 counts/frame, at 20 msec/frame with 5% gate tolerance. LV regional analysis was performed using a computer algorithm written by the authors running on Digital PDP 11/34 machine. The algorithm after having identified the center of gravity of the LV, divided it into 4, 5 and 6 equiangular sectors. In the 5, and 6 sector analysis, the region including the mitral and aortic valves was excluded from subsequent analysis. In each sector Ejection Fraction (EF) and Peak Filling Rate (PFR) were computed. In addition, the Time to End Systole (TES) and Time to Peak Filling Rate were also assessed for each region. The coefficient of variation of the regional values of TES (CV-TES) and regional TPFR (CV-TPFR) were then computed and considered as indices of LV systolic (CV-TES) and diastolic (CV-TPFR) asynchrony. Repeatability was firstly assessed by linear regression analysis between the 2 RNA studies. Our data show a high correlation coefficient on regional values of EF and PFR (R: > 0.92). Moreover, the differences in a given parameter between the 2 studies were plotted against their mean value, and the coefficient of repeatability (CR) was calculated as twice the standard deviation of the differences. No significant differences were found between EF and PFR regional values in the 2 RNA studies (EF coefficient of repeatability: < 0.18; PFR coefficient of repeatability: < 0.8). A low value of coefficient of repeatability was found also for CV-TES (< 17) and for CV-TPFR (< 18). In conclusion LV regional analysis is a repeatable method of analysis, and the number of regions does not affect the repeatability.

Angiocardiography↗
PubMed1994

Modulation of platelet function by reactive oxygen metabolites.

Reactive oxygen metabolites have been reported to affect platelet aggregation. However, this phenomenon is still poorly understood. In the present study we investigated the effects of superoxide radical and hydrogen peroxide (H2O2) on platelet function in vitro and correlated those effects to possible changes of platelet concentrations of cyclic nucleotides and thromboxane, since these systems play a key role in the response of platelets to activating stimuli. Human platelets were exposed to xanthine-xanthine oxidase (X-XO), a system that generates both superoxide radicals and H2O2. Sixty seconds of incubation with X-XO impaired aggregation in response to ADP (by 48%), collagen (by 71%), or the thromboxane mimetic U-46619 (by 50%). This effect was reversible and occurred in the absence of cell damage. Impairment of aggregation in platelets exposed to X-XO was due to H2O2 formation, since it was prevented by catalase but not by superoxide dismutase. Similarly, incubation with the pure H2O2 generator glucose-glucose oxidase also markedly inhibited ADP-induced platelet aggregation in a dose-dependent fashion. Impaired aggregation by H2O2 was accompanied by a > 10-fold increase in platelet concentrations of guanosine 3',5'-cyclic monophosphate (cGMP), whereas adenosine 3',5'-cyclic monophosphate levels remained unchanged. The inhibitory role of increased cGMP formation was confirmed by the finding that H2O2-induced impairment of platelet aggregation was largely abolished when guanylate cyclase activation was prevented by incubating platelets with the guanylate cyclase inhibitor, LY-83583. Different effects were observed when arachidonic acid was used to stimulate platelets. Exposure to a source of H2O2 did not affect aggregation to arachidonate. Furthermore, in the absence of exogenous H2O2, incubation with catalase, which had no effects on platelet response to ADP, collagen, or U-46619, virtually abolished platelet aggregation and markedly reduced thromboxane B2 production (to 44% of control) when arachidonic acid was used as a stimulus. In conclusion, our data demonstrate that H2O2 may exert complex effects on platelet function in vitro. Low levels of endogenous H2O2 seem to be required to promote thromboxane synthesis and aggregation in response to arachidonic acid. In contrast, exposure to larger (but not toxic) concentrations of exogenous H2O2 may inhibit aggregation to several agonists via stimulation of guanylate cyclase and increased cGMP formation.

Adenine Nucleotides↗
PubMed1994

Forearm vascular responsiveness to alpha 1- and alpha 2-adrenoceptor stimulation in patients with congestive heart failure.

BACKGROUND: The alpha-adrenergic component of the sympathetic nervous system plays a major role in the pathophysiology, clinical manifestations, and natural history of human congestive heart failure (CHF). However, the functional integrity of vascular alpha 1- and alpha 2-adrenoceptors in CHF remains to be elucidated. The present study was designed to assess the vascular responsiveness of alpha 1- and alpha 2-adrenoceptors in patients with CHF. METHODS AND RESULTS: To evaluate alpha 1- and alpha 2-adrenoceptor responsiveness, we studied the effects of the regional infusion into the brachial artery of increasing doses of phenylephrine (a selective alpha 1-adrenoceptor agonist) and BHT 933 (a selective alpha 2-adrenoceptor agonist) on vascular responses in 12 healthy subjects and in 24 patients with CHF secondary to primary dilated cardiomyopathy or ischemic heart disease. Left ventricular ejection fraction was measured by radionuclide angiography, and forearm blood flow was determined by venous occlusion plethysmography. Phenylephrine reduced forearm blood flow in normal subjects from 5.2 +/- 0.9 to 2.5 +/- 0.6 mL per 100 mL of tissue/min (P < .05) at the highest dose (-50.8 +/- 4.8% versus baseline). A similar vasoconstriction was obtained in patients with CHF (from 3.5 +/- 0.5 to 1.5 +/- 0.2 mL per 100 mL of tissue/min (P < .05) (-58.7 +/- 5.0% versus baseline). The dose-response curves produced by phenylephrine in the two groups were comparable. The highest dose of BHT 933 reduced forearm blood flow in normal subjects from 5.3 +/- 0.9 to 2.3 +/- 0.6 mL per 100 mL of tissue/min (P < .05) (-59.0 +/- 4.9% versus baseline). In patients with CHF, a similar vasoconstriction was obtained (from 4.2 +/- 0.8 to 1.5 +/- 0.3 mL per 100 mL of tissue/min, P < .05, -62.1 +/- 6.5% versus baseline). The dose-response curves produced by BHT 933 also were comparable in the two groups. In patients with CHF, plasma concentrations of norepinephrine were significantly higher than in normal subjects. CONCLUSIONS: The results of the present study demonstrate that alpha 1- and alpha 2-adrenoceptor stimulations produced an equivalent vasoconstriction in patients with CHF and in normal subjects. This indicates that the vascular responsiveness to alpha-adrenoceptor agonists may be preserved in the limb vessels of patients with CHF.

Adrenergic alpha-Agonists↗
PubMed1994

A monoclonal antibody against rabbit tissue factor inhibits thrombus formation in stenotic injured rabbit carotid arteries.

Tissue factor (TF) is a transmembrane protein that binds factor VII/VIIa, thus activating the extrinsic blood coagulation pathway. Since this pathway appears to be involved in the formation of intravascular thrombi, the anti-rabbit TF monoclonal antibody, AP-1, was produced and tested as an antithrombotic agent in a rabbit model of recurrent intravascular thrombosis. In this model, a plastic constrictor is positioned around the injured rabbit carotid arteries, and flow is monitored with a Doppler flow probe. This produces cyclic flow variation (CFV) in the carotid artery, which is caused by recurrent formation and dislodgment of thrombi at the site of the stenosis. After monitoring CFV pattern for 30 minutes, AP-1 was infused intravenously into nine rabbits at doses of 0.05 to 1.5 mg/kg body weight, and a control monoclonal antibody that does not react with rabbit TF was infused into four additional rabbits. In all rabbits receiving AP-1, CFV was abolished, and a steady normal blood flow was restored, indicating that thrombus formation had been blocked by AP-1. By contrast, in all rabbits that received the control monoclonal antibody, CFV continued unaltered. There was no change in the partial thromboplastin time and ex vivo platelet aggregation to several different agonists after infusion of AP-1, indicating an absence of systemic effects on the coagulation process. We conclude that activation of the extrinsic coagulation pathway has a key role in triggering intravascular thrombosis and that an anti-TF monoclonal antibody is an effective antithrombotic agent that could have therapeutic potential for humans.

Animals↗
PubMed1994

Oxygen radicals inhibit human plasma acetylhydrolase, the enzyme that catabolizes platelet-activating factor.

Platelet-activating factor (PAF) can exert profound inflammatory effects at very low concentrations. In plasma, PAF is hydrolyzed to lyso-PAF by acetylhydrolase, an enzyme that circulates bound to LDL. Previous studies suggest that oxygen radicals may act synergistically with PAF to potentiate tissue injury. However, mechanisms underlying this interaction have not been elucidated. In this study we investigated whether oxygen radicals may inactivate PAF acetylhydrolase. PAF acetylhydrolase activity was measured in human plasma and purified LDL before and after exposure to radicals (10-20 nmol/min per ml) generated by xanthine/xanthine oxidase. Oxygen radicals induced > 50% loss of PAF acetylhydrolase activity within 60 s and almost complete inactivation by 10 min. This phenomenon was irreversible and independent of oxidative modification of LDL. Inactivation occurred without changes in the affinity constant of the enzyme (Km was 17.9 microM under control conditions and 15.1 microM after exposure to oxygen radicals). Inactivation was prevented by the scavengers superoxide dismutase or dimethylthiourea or by the iron chelator deferoxamine. Thus, superoxide-mediated, iron-catalyzed formation of hydroxyl radicals can rapidly and irreversibly inactivate PAF acetylhydrolase. Since concomitant production of PAF and oxygen radicals can occur in various forms of tissue injury, inactivation of acetylhydrolase might represent one mechanism by which oxygen radicals may potentiate and prolong the proinflammatory effects of PAF.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed1994

[Interstitial changes and ventricular hypertrophy in man].

Left ventricular hypertrophy is accompanied by the remodeling of the collagen network. We have studied collagen network in left ventricular hypertrophy secondary to aortic stenosis by cardiac catheterization and endomyocardial biopsies. We have demonstrated that collagen architecture is abnormal in 2/3 of patients with aortic stenosis and is more important than collagen concentration in influencing myocardial stiffness and ejection fraction. Furthermore, we observed that relaxation and asynchrony were influenced by the degree of hypertrophy instead of by the collagen network. The postoperative regression of left ventricular hypertrophy and the changes in interstitial tissue after valve replacement have been studied in a subgroup of patients. The major finding is that the regression of myocardial hypertrophy is a process that occurs over many years after correction of primary hemodynamic abnormality. Six to 7 years after valve replacement we observed, together with the normalization of diastolic stiffness, the complete normalization of interstitial fibrosis that was primarily increased (both pre and early postoperatively).

Adult↗
PubMed1994

[Coronary angioplasty for the recovery of myocardial function after acute myocardial infarction: mid- and long-term results].

Sixty-three patients with previous myocardial infarction and documented hypoperfused reversibly dysfunctional myocardium after 201thallium tomography and/or echo-dobutamine were candidates to coronary angioplasty. Patients were enrolled at four hospitals (Naples, Milan, Pisa and Varese) and evaluated by different study protocols, while endpoint (presence of myocardial viability and efficacy of coronary angioplasty to improve dysfunctional myocardium) was similar. Sixty-two patients underwent successful angioplasty, and early evaluation (between 1 and 3 months after procedure) showed the ability of either 201thallium tomography and/or dobutamine echocardiography, to identify hypoperfused reversibly dysfunctional myocardium. Ten patients underwent late (after 8 +/- 2 months) evaluation of both wall motion and myocardial perfusion showing a sustained improvement in 25/32 hypoakinetic myocardial segments. Our data confirm the efficacy of revascularization of hypoperfused dysfunctional myocardial segments by coronary angioplasty. Further studies are warranted to obtain a better patient stratification and to evaluate the long-term results.

Adult↗
PubMed1994

[Gene therapy for the treatment of restenosis after coronary angioplasty].

Accumulation and proliferation of vascular smooth muscle cells are associated with atherosclerosis and hypertension. Proliferation of smooth muscle cells constitutes a major pathological event responsible for long-term failure of coronary and peripheral arterial bypass graft as well as the development of restenosis after percutaneous transluminal coronary angioplasty (PTCA). The incidence of restenosis after PTCA has been reported to be as high as 40-45% within 3-6 months. Major advantages in recombinant deoxyribonucleic acid (DNA) technology and eukaryotic gene regulation allow to hypothesize gene therapy as a potential treatment for inherited and acquired diseases. Gene therapy is the introduction of genes into somatic cells to correct an inherited or acquired disorder through the synthesis of missing or defective protein. Although no disease has yet been treated by gene therapy, several gene transfer protocols have recently been undertaken. We have studied the expression of foreign DNA that has been introduced into smooth muscle cells after balloon carotid injury in a rat model of angioplasty. The effects of different degree of balloon injury on neointima formation and c-fos expression was also assessed. Our data demonstrate that site-specific gene expression can be achieved by direct gene transfer in vivo and could be applied to the treatment of restenosis after PTCA.

Angioplasty, Balloon, Coronary↗