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Biomedical subjects

F Andreotti

Publications and source records attributed to F Andreotti.

At least 73 records · Page 4Linked to original sources

Gall stone pulverisation strategy in patients treated with extracorporeal lithotripsy and follow up results of maintenance treatment with ursodeoxycholic acid.

Between November 1988 and July 1992 70 patients with radiolucent gall stones were treated with extracorporeal lithotripsy (ESL) and ursodeoxycholic acid (UDCA; mean (SD) dose 11.2 (1.9) mg/kg/day). Fifty three patients have been followed for one year. One week after lithotripsy, 30.6% had completely eliminated all stone fragments from the gall bladder and one year later 93.9% were free of stones. Three factors were considered important in achieving these results. 'Pulverisation' of the stone--that is, its fragmentation into echogenic dust (crystalline aggregates, some few hundred mu in size) or particles similar to grains of sand, smaller than 1 mm in diameter, or both, is required. Secondly, dust and particles were rapidly eliminated, strongly suggesting a mechanical elimination process by physiological gall bladder contractions. Thirdly, there must be chemical dissolution with biliary acids. This therapeutic approach gave excellent results without causing any clinically relevant side effects. The first 20 patients who became free of stones after ESL were given oral bile acid maintenance treatment--300 mg/day of UDCA at bedtime, for two years. All were asymptomatic and none had suffered a recurrence after two years. In four patients, crystalline aggregates, detected in gall bladder bile by ultrasound, were subsequently dissolved between one and three months after resuming a full dose regimen of UDCA.

Adult↗

Angiotensin II increases plasminogen activator inhibitor type 1 and tissue-type plasminogen activator messenger RNA in cultured rat aortic smooth muscle cells.

BACKGROUND: The role of angiotensin as a vasoconstrictor is well established. Lately, several other actions of this hormone on vascular smooth muscle (VSM) cells have been recognized including the induction of hypertrophy and/or DNA synthesis. Platelet-derived growth factor (PDGF), a mitogen recently shown to increase plasminogen activator inhibitor type 1 (PAI-1) synthesis in VSM cells, shares with angiotensin II (Ang II) several steps of its intracellular signaling pathway. METHODS AND RESULTS: The expression of PAI-1 and tissue-type plasminogen activator (TPA) mRNA in cultured rat VSM cells was studied. Northern blot analysis demonstrated a severalfold increase in the PAI-1 mRNA 3 to 8 hours after stimulation with 300 nmol/L Ang II. A similar response for TPA mRNA was observed. This induction did not require the synthesis of an intermediate protein or peptide because it was not affected by cycloheximide. In the cell-conditioned supernatant, the net result was an increase in PAI-1 activity from 4.18 +/- 1.8 to 13.2 +/- 6.8 IU/mL 6 hours after the addition of 300 nmol/L Ang II (mean +/- SD, P < or = .008, n = 6). The Ang II-induced increase in PAI activity was dose related, with a maximal effect at a concentration of 23 nmol/L (n = 3) and an ED50 of 3.3 +/- 1.5 nmol/L (n = 3). [Sar1-Ile8]angiotensin II, a specific competitive antagonist of Ang II, blocked 90 +/- 9% (n = 3) of the PAI activity induced by 10 nmol/L Ang II. In basal conditions, fibrin overlay zymography demonstrated the presence of free TPA. After stimulation with Ang II, lysis caused by the in situ dissociation of TPA was also present in the region of the TPA/PAI-1 complex. Angiotensin I (Ang I) elicited an increase in PAI activity similar to that obtained with equivalent doses of Ang II. Captopril (5 micrograms/mL), an inhibitor of the angiotensin-converting enzyme (ACE), completely prevented the Ang I effect, demonstrating that VSM cells display an ACE-like activity. CONCLUSIONS: Recent research has demonstrated the existence of a localized vascular renin-angiotensin system. The finding that Ang II can potentially modulate the plasminogen activation in the arterial wall has important biological and therapeutical implications for the evolution of arterial wall thrombi and the migration of cells through the vessel wall in the genesis of atherosclerotic lesions. We speculate that the reduction in thrombotic events observed in patients with a previous myocardial infarction and in high-renin, hypertensive patients treated with ACE inhibitors could be due at least in part to the decreased production of PAI-1 by VSM cells caused by these agents.

Amino Acids↗

[Interactions between atherosclerosis and ischemic stimuli in the pathogenesis of acute coronary syndromes].

Until a few years ago coronary atherosclerosis was thought to be a slowly progressive disease eventually leading to total coronary occlusion and myocardial infarction. Recent angiographic studies have shown, instead, that mild or moderate coronary stenoses have the highest risk of causing acute coronary syndromes when complicated by thrombus formation which, in turn, appears to be due to a complex interaction between the atherosclerotic background and acute ischemic stimuli. The tendency of the atherosclerotic background to develop thrombosis may be different in different patients, as indicated by the observation that the risk factor profile of patients who present with chronic coronary syndromes is different from that of patients who present with acute syndromes. The acute ischemic stimuli so far identified are: a sudden local thrombogenic stimulus; a transient systemic increase in systemic pro-coagulant activity; a transient increase in proximal and/or distal coronary tone. The recent observation of inflammatory cells activation, including T-lymphocytes, in patients with acute ischemic syndromes raises the intriguing possibility that a specific antigenic stimulus may play an important pathogenetic role.

Arteriosclerosis↗

[Antithrombin therapy in acute coronary syndromes].

Intracoronary thrombosis is fundamental in the pathogenesis of acute coronary syndromes, although the causes of thrombosis are still unclear. As thrombin generation is crucial for thrombus formation, the inhibition of thrombin is a primary aim to prevent the evolution of an initial repair process into a pathological thrombus. Thrombin inhibition can be achieved by several drugs. Heparin is the principal antithrombin drug currently used in acute syndromes; it acts mainly by binding to antithrombin III and increasing its inhibitory effect on thrombin and other coagulation factors. The heparin-antithrombin III complex, however, does not inhibit thrombus-bound thrombin; moreover, iv heparin requires frequent laboratory monitoring and dose adjustments. Despite these limitations, continuous infusion of i.v. heparin has been found to be effective in unstable angina and in myocardial infarction, especially when treated with accelerated rt-PA. New antithrombin drugs that selectively and directly inhibit thrombin are hirudin, its synthetic derivate hirulog, and argatroban. These drugs have several theoretical advantages over heparin: greater stability of the aPTT--with the need for less laboratory monitoring--and greater efficacy--associated mainly with its capacity to inhibit clot-bound thrombin. Clinical pilot studies seem to indicate a greater antithrombotic efficacy compared with heparin, but a greater number of hemorrhagic events in patients with acute myocardial infarction receiving thrombolysis. In conclusion, the use of heparin is certainly indicated in patients with unstable angina and persistent ischemia and in acute myocardial infarction treated with accelerated rt-PA. The use of new antithrombin drugs, although promising, requires further clinical evaluation.

Acute Disease↗

Aspirin, but not heparin, suppresses the transient increase in thromboxane biosynthesis associated with cardiac catheterization or coronary angioplasty.

OBJECTIVES: We sought to study the dose dependence of in vivo suppression by aspirin of enhanced thromboxane biosynthesis in the setting of coronary angioplasty and to evaluate the effects of heparin and aspirin during cardiac catheterization. BACKGROUND: Percutaneous transluminal coronary angioplasty induces a controlled injury of the intima of the diseased arterial segment, with rapid deposition of platelets at the site of dilation. Thus, it provides a clinical model of intracoronary platelet activation. METHODS: The urinary excretion of a major enzymatic metabolite of thromboxane A2, 11-dehydro-thromboxane B2, was measured in 57 patients with stable coronary artery disease undergoing cardiac catheterization (n = 28) or elective single-vessel percutaneous transluminal coronary angioplasty (n = 29). Three consecutive urine collections were obtained from all patients before during and after either procedure. Patients undergoing catheterization were treated with the following regimens: a) no aspirin for > or = 10 days and no heparin (n = 12); b) no aspirin for > or = 10 days but heparin, 10,000 IU, at the time of catheterization (n = 5); c) aspirin, 300 mg/day, for at least 5 days (n = 11). Patients undergoing coronary angioplasty were randomly assigned to short-term treatment with aspirin given as a) 75 mg/day for > or = 5 days before angioplasty (n = 11); b) 300 mg/day for > or = 3 days before angioplasty (n = 9); or c) 300 mg/day for > or = 3 days before angioplasty followed by 1,000 mg during angioplasty (n = 9). RESULTS: In patients undergoing catheterization, urinary 11-dehydro-thromboxane B2 excretion (pg/mg creatinine) increased from 563 +/- 481 (mean +/- SD) to 1,684 +/- 1,332 in the absence and from 620 +/- 191 to 1,588 +/- 597 in the presence of heparin. No increase was observed in the group receiving aspirin (from 240 +/- 141 to 215 +/- 115). In patients undergoing coronary angioplasty treated with aspirin, 75 mg/day, urinary 11-dehydro-thromboxane B2 averaged 180 +/- 112, 223 +/- 178 and 294 +/- 260, respectively, before, during and after the procedure. At 300 mg/day, the corresponding values were 185 +/- 48, 217 +/- 70 and 197 +/- 93. In patients also receiving aspirin, 1,000 mg, during angioplasty, 11-dehydro-thromboxane B2 averaged 151 +/- 66, 138 +/- 43 and 133 +/- 77, respectively. CONCLUSIONS: Enhanced thromboxane biosynthesis associated with cardiac catheterization or coronary angioplasty can be largely suppressed by low dose aspirin. This finding is consistent with the view that this alteration reflects platelet activation.

Aged↗

Von Willebrand factor, plasminogen activator inhibitor-1 and C-reactive protein are markers of thrombolytic efficacy in acute myocardial infarction.

Plasma von Willebrand factor, plasminogen activator inhibitor activity and C-reactive protein were assessed as markers of coronary recanalisation in 30 patients with acute myocardial infarction receiving tissue-type plasminogen activator (t-PA). Blood samples were taken before t-PA (time 0), 4-hourly for 24 h and daily up to 72 h. A continuous electrocardiogram was recorded in the first 24 h. Coronary arteriography was performed 90 min and 24 h after the start of t-PA. Patients with a patent infarct artery (n = 17), compared to those with occluded artery (n = 13), showed a fall in von Willebrand factor from 0 to 24 h (p = 0.001), a greater fall in plasminogen activator inhibitor from 24 to 48 h (p = 0.04) and a fall in C-reactive protein from 48 to 72 h (p = 0.002). The accuracy of these indices compared favourably with time to peak plasma MB creatine kinase and > or = 50% resolution of maximal ST-deviation on the electrocardiogram. Thus, changes in plasma von Willebrand factor, plasminogen activator inhibitor and C-reactive protein during the first 3 days of myocardial infarction are indicative of thrombolytic efficacy. Their concordant behaviour may reflect a common regulatory mechanism.

Adult↗

Effectiveness and safety of a single intravenous bolus injection of tissue-type plasminogen activator in acute myocardial infarction. Bolus Dose-Escalation Study of Tissue-Type Plasminogen Activator (BEST) Investigators.

The efficacy of multiple intravenous bolus injections of tissue-type plasminogen activator (t-PA) in inducing rapid coronary recanalization in patients with acute myocardial infarction was previously demonstrated. In this Bolus Dose-Escalation Study of Tissue-Type Plasminogen Activator (BEST), the efficacy of 3 different doses of a single rapid intravenous bolus injection of t-PA (dute-plase, Wellcome Foundation, London) in inducing coronary patency (Thrombolysis In Myocardial Infarction perfusion grade 2 or 3) in 64 patients with acute myocardial infarction presenting less than 6 hours after onset of symptoms was investigated. At 60 minutes after administration of t-PA, the infarct-related coronary artery was patent in 9 of 17 patients (53%; 95% confidence interval [CI] 28 to 77%) after 0.3 MU/kg, in 14 of 23 (61%; 95% CI 39 to 80%) after 0.45 MU/kg and in 10 of 14 (71%; 95% CI 42 to 92%) after 0.6 MU/kg. At 90 minutes after t-PA, coronary patency was present in 9 of 17 cases (53%; 95% CI 28 to 77%) after 0.3 MU/kg, in 12 of 24 (50%; 95% CI 29 to 71%) after 0.45 MU/kg and in 10 of 13 (77%; 95% CI 46 to 95%) after 0.6 MU/kg. One patient in each dose group had a silent reoccluded infarct-related artery by 24 hours, and there were 2 clinical reinfarctions before discharge. No major bleeding events were observed. There were 5 hospital deaths, all unrelated to t-PA. A single intravenous bolus injection of 0.6 MU/kg of t-PA appears to be effective in inducing rapid coronary patency and to be safe in patients with acute myocardial infarction.

Adult↗

Effect of propranolol (long-acting) on the circadian fluctuation of tissue-plasminogen activator and plasminogen activator inhibitor-1.

The incidence of myocardial infarction and sudden cardiac death is highest in the morning. Inhibition of fibrinolytic activity in blood also peaks in the morning and this inhibition may favor the development of arterial thrombosis. It has been reported that patients treated with beta blockers do not show the typical circadian pattern of onset of myocardial infarction and sudden cardiac death. This study was undertaken to investigate whether beta blockade alters the circadian rhythm of 2 major fibrinolytic factors, tissue-plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1). Repeated blood samples were taken over a 24-hour period in 13 healthy volunteers: 7 taking 160 mg/day of long-acting propranolol orally for 14 days, and the other 6 taking no medications. Blood samples were analyzed for the plasma levels of t-PA activity, t-PA antigen, PAI activity and PAI-1 antigen. A significant circadian variation of all 4 parameters was present in both groups. No significant differences in peak and nadir values, 24-hour mean, amplitude of fluctuation, and time of peak and nadir were found between the treated and untreated subjects. The data therefore suggest that propranolol treatment does not affect the plasma concentrations at rest or the endogenous circadian rhythm of t-PA and PAI-1 in healthy volunteers. The reported alteration in the circadian pattern of onset of myocardial infarction and sudden cardiac death by beta blockers does not appear to be mediated by effects on the fibrinolytic system.

Adult↗

Circadian variation of fibrinolytic activity in blood.

Approximately 35 years ago, it was discovered that spontaneous fibrinolytic activity in blood showed a sinusoidal variation with a period of 24 h; it increased severalfold during the day, reaching a peak at 6:00 p.m. and then dropped to trough levels at 3:00-4:00 a.m. The range of the fluctuation and the 24-h mean levels were highly reproducible within an individual; moreover, the timing of the oscillation was remarkably consistent among individuals, with a fixed phase relationship to external clock time. The biorhythm could not be accounted for simply by variations in physical activity, body posture, or sleep/wake schedule. Gender, ethnic origin, meals, or resting levels of blood fibrinolytic activity also did not influence the basic features of the rhythm. Older subjects, compared to younger ones, showed a blunted diurnal increase in fibrinolytic activity in blood. Recent studies have established that, of the known components of the fibrinolytic system, only tissue-type plasminogen activator (tPA) and its fast-acting inhibitor, plasminogen activator inhibitor-1 (PAI-1), show a marked circadian variation in plasma. In contrast, levels of plasminogen, alpha 2-antiplasmin, urinary-type plasminogen activator, and a reversible tPA inhibitor vary little or none during the 24 h. Quenching antibodies to tPA have shown that the circadian rhythm of fibrinolytic activity in blood is due exclusively to changes in tPA activity. However, the 24-h fluctuation of plasma tPA activity is phase shifted in relation to the rhythm of immunoreactive tPA, but shows a precise phase inversion with respect to the 24-h variation of PAI-1 activity and antigen. Therefore, plasma tPA activity, as currently measured in vitro, is tightly and inversely related to the levels of PAI-1 throughout the 24-h cycle. The factors controlling the rhythmicity of plasma PAI-1 are not fully elucidated but probably involve a humoral mechanism; changes in endothelial function, circulating platelet release products, corticosteroids, catecholamines, insulin, activated protein C, or hepatic clearance do not appear to be responsible. Shift workers on weekly shift rotations show a disrupted 24-h rhythm of plasma tPA and PAI-1. In acute and chronic diseases, the circadian rhythmicity of fibrinolytic activity may show a variety of alterations, affecting the 24-h mean, the amplitude, or the timing of the fluctuation. It is advisable, therefore to define the 24-h pattern of plasma tPA and PAI-1 in patient groups, before levels based on a single blood sampling time are compared to those of a control population.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗

Effectiveness of multiple bolus administration of tissue-type plasminogen activator in acute myocardial infarction.

The feasibility and possible advantages of intravenous bolus administration of recombinant tissue-type plasminogen activator (rt-PA) were investigated in 26 consecutive patients with early (less than 6 hours) evolving acute myocardial infarction. Either an intravenous infusion of 40 clot-lysis megaunits (cIMU) double-chain rt-PA over 1.5 hours followed by 20 cIMU over 5 hours (infusion group, n = 12) or 4 intravenous bolus injections of 10 cIMU at 20 minute intervals (bolus group, n = 14) were randomly administered. Coronary arteriography was performed before and at regular predefined intervals up to 90 minutes from the start of rt-PA administration, and at 24 hours. Acute recanalization of the infarct-related coronary artery was demonstrated in 7 of 12 patients (58%; 95% confidence interval 28 to 85%) in the infusion group and 11 of 14 patients (79%; 95% confidence interval 49 to 95%) in the bolus group (difference not significant). Two patients in the bolus group had reoccluded by 24 hours. Mean time from the start of rt-PA to patency of the infarct-related coronary artery was 39 +/- 6 (standard error of the mean) minutes in the infusion group and 28 +/- 6 minutes in the bolus group (p = 0.2). There were no significant differences in the minimum infarct-related coronary artery luminal diameter measured by computerized quantitative arteriography between the infusion group and the bolus group at 90 minutes or at 24 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

Early coronary reperfusion blunts the procoagulant response of plasminogen activator inhibitor-1 and von Willebrand factor in acute myocardial infarction.

The effects of early coronary recanalization on the plasma levels of two procoagulant acute phase proteins, the fastacting plasminogen activator inhibitor and von Willebrand factor, were investigated in 24 patients with myocardial infarction receiving intravenous recombinant tissue-type plasminogen activator (rt-PA) within 6 h of the onset of symptoms. Coronary angiography was performed before and 90 min after the start of rt-PA infusion. Continuous electrocardiographic recordings and 4 h plasma creatine kinase MB isoenzyme (CK MB) were performed over the first 24 h. Plasma plasminogen activator inhibitor activity, von Willebrand factor and C-reactive protein were measured before rt-PA infusion, daily for the first 3 days and after 90 days. In the entire group, plasminogen activator inhibitor activity peaked at 24 h (day 1), representing a significant increase over values at all other times (p = 0.03). von Willebrand factor was higher in the first 2 days of infarction compared with after 90 days (p = 0.001). C-reactive protein peaked on day 2, with an eightfold increase over values on admission (p = 0.001). In the 16 patients with a patent infarct-related artery at 90 min, infarct size estimated by integrated 24 h CK MB, time for ST segment elevation to decrease to half-maximum and peak C-reactive protein were reduced significantly by more than twofold compared with values in the 8 patients with an occluded artery at 90 min. The patients with early recanalization also had lower plasminogen activator inhibitor activity on day 2 (p = 0.05) and day 3 (p = 0.02) and lower 0 to 72 h averaged von Willebrand factor (p = 0.01). Thus, early coronary recanalization curtails the response of plasminogen activator inhibitor activity and von Willebrand factor to myocardial infarction, most likely by reducing the extent of ischemia and necrosis and the consequent acute phase reaction. By blunting the early postinfarction procoagulant state, prompt recanalization may reduce the risk of thromboembolic complications in the first days after myocardial infarction.

C-Reactive Protein↗

The contribution of ventricular tachyarrhythmias to the genesis of cardiac pain during transient myocardial ischaemia in patients with variant angina.

The 24-h ambulatory electrocardiograms of 15 patients with both variant angina and ischaemia-related arrhythmias were analyzed to correlate cardiac pain with the following variables: site, type, duration and magnitude of ECG changes, presence and type of arrhythmias and time of occurrence of ischaemic attacks during the 24-h. Apart from sublingual nitrate therapy, Holter monitoring was performed in the Coronary Care Unit (CCU), in the drug-free state in all patients. During a total of 79 days of monitoring, patients had 1385 ischaemic episodes, of which only 30% were painful. The site of ischaemia did not predict the occurrence of pain. Pain was more frequently associated with ST-segment elevation, longer ischaemic duration, increased time to peak ECG change, and greater ST-segment shift and arrhythmias. When the 259 attacks in association with ventricular arrhythmias were compared to the arrhythmia-free episodes, they were more frequently painful for the same duration and magnitude of ECG ischaemic changes. Furthermore, the complexity of arrhythmias increased the probability of cardiac pain. Most ischaemic episodes occurred at night and a decrease in the frequency of painful episodes (apart from those associated with arrhythmias) was apparent. Thus, in addition to electrocardiographic severity and duration of ischaemia, the presence of ventricular arrhythmias and the time of occurrence seem to influence pain perception during ischaemia.

Adult↗

Factors affecting regional pulmonary blood flow in chronic ischemic heart disease.

To assess the effect of left heart disease on pulmonary blood flow distribution, we measured mean pulmonary arterial and wedge pressures, cardiac output, pulmonary vascular resistance, pulmonary blood volume, and arterial oxygen tension before and after treatment in 13 patients with longstanding ischemic heart failure and pulmonary edema. Pulmonary edema was evaluated by a radiographic score, and regional lung perfusion was quantified on a lung scan by the upper to lower third ratio (U:L ratio) of pulmonary blood flow per unit of lung volume. In all cases, redistribution of lung perfusion toward the apical regions was observed; this pattern was not affected by treatment. After treatment, pulmonary vascular pressures, resistance, and edema were reduced, while pulmonary blood volume did not change. At this time, pulmonary vascular resistance showed a positive correlation with the U:L ratio (r = 0.78; P less than 0.01), whereas no correlation was observed between U:L ratio and wedge pressure, pulmonary edema, or arterial oxygen tension. Hence, redistribution of pulmonary blood flow, in these patients, reflects chronic structural vascular changes prevailing in the dependent lung regions.

Blood Volume↗

Detection of spontaneous episodes in post-infarction angina. Comparison between CCU and Holter monitoring.

The objects of this study are: to evaluate the incidence of early post-infarction angina in patients who developed transmural infarction (Q-AMI) or sub-endocardial infarction (no Q-AMI) during hospitalization; to compare data obtained from patients monitored in Coronary Care Unit (CCU) with those obtained from Holter monitoring. The 107 patients under study (55 with Q-AMI and 52 with no Q-AMI) presented the acute event on average 7.4 and 5.1 days after admittance in the CCU, respectively. A history of angina was present in all except 1 patient with Q-AMI and in all with no Q-AMI. After AMI the angina disappeared in 22 of the patients with Q-AMI and in 31 with no Q-AMI, while it continued in 33 and 21 of these patients, respectively. Twenty-one patients underwent ECG recording according to the Holter technique while in CCU, for an average of 4.4 days before and 5.2 days after the onset of AMI. The comparative analysis of the results obtained from the CCU and from Holter monitoring shows that the CCU greatly underestimates the number of ischaemic episodes, even when pain is present (4.5 episodes per patient per day before AMI and 2 after, versus 13.7 and 6.8 with Holter monitoring). The number of ventricular arrhythmias also seemed lower when analysing data from CCU monitoring. These data demonstrate the importance of Holter monitoring, even in patients admitted to a CCU, for a precise evaluation of the ischaemic and arrhythmic phenomena.

Adult↗