Molecular typing of transmissible spongiform encephalopathy from Italian disease outbreaks in small ruminants.
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Animals↗
Biomedical subjects
S Nodari
Publications and source records attributed to S Nodari.
Glucagon-like peptide 1 (GLP-1) secretion and plasma dipeptidyl peptidase IV (DPP-IV) activity in morbidly obese patients undergoing biliopancreatic diversion.
BACKGROUND: The physiological inhibitory control of glucagon-like Peptide 1 (GLP-1) on gastric emptying and the contribution of this peptide in the regulation of food intake as a satiety factor suggest that impaired secretion and/or activity of GLP-1 may be involved in the pathogenesis of obesity. We investigated food-mediated GLP-1 secretion as well as plasma activity of dipeptidyl-peptidase IV (DPP-IV), the enzyme responsible for rapid inactivation of the circulating peptide, in morbidly obese patients, before and after weight loss resulting from biliopancreatic diversion. METHODS: Twenty-two morbidly obese non-diabetic patients (BMI = 47.5 +/- 1.8) and 9 age-matched healthy volunteers were studied. A mixed meal (700 kcal) was administered to all subjects and blood samples were collected at 0, 15, 30, 60, 120 min for the determination of circulating glucose, insulin, GLP-1 (7 - 36 amide) concentrations and plasma DPP-IV activity. The patients repeated the test meal after 50 % overweight reduction resulting from surgical treatment (BMI = 33.8 +/- 1.1). RESULTS: While nutrient ingestion significantly increased plasma GLP-1 levels in the control group (30', 60': p < 0.01), the test-meal failed to modify basal peptide values in the obese patients, and an overall reduction in circulating GLP-1 occurred during the observation period (p < 0.001). Plasma DPP-IV activity in the same patients resulted as being significantly higher than controls, both at fasting and in response to the meal (p < 0.05). With respect to preoperative values, an overall increase in circulating GLP-1 levels occurred in all patients following biliopancreatic diversion (p < 0.001). Plasma DPP-IV activity, on the other hand, continued to be abnormally increased, even after considerable weight loss (p < 0.05 vs. controls). CONCLUSIONS: First: In morbid obesity, the accelerated inactivation of circulating GLP-1 could at least partially account for plasma peptide levels lower than normal, the defective availability of such a satiety factor possibly contributing to eating behaviour abnormalities; Second: plasma DPP-IV hyperactivity in the obese did not seem to be affected by the overweight degree, the increase in postoperative GLP-1 levels mainly resulting from hyperstimulation of GLP-1 secretory cells due to surgical manipulation of gastrointestinal tract. If the abnormally accelerated degradation of GLP-1 in obesity is confirmed, selective DPP-IV inhibitors could actually represent an ideal approach to obesity management.
Adult↗
Beta-blockade in heart failure: selective versus nonselective agents.
Controlled clinical trials performed in more than 13 000 patients have, to date, consistently shown the beneficial effects of long term beta-adrenoceptor antagonist (beta-blocker) therapy in patients with chronic heart failure. It is not clear whether this represents a class effect or whether it is specific only to some agents. Beneficial effects on the prognosis of patients with mild to moderate heart failure have been shown with metoprolol, bisoprolol, and carvedilol. These beta-blockers, however, differ in their pharmacologic characteristics. Metoprolol and bisoprolol are selective for beta(1)-adrenergic receptors and are devoid of ancillary properties. Carvedilol, at a dosage of 50 mg/day, blocks all beta(1)-, beta(2)-, and alpha(1)-adrenergic receptors, and it has associated antiproliferative and antioxidant activities. These differences cause a varied acute hemodynamic response, with a reduction in cardiac output and a tendency toward a rise in pulmonary wedge pressure with selective agents and no change in cardiac output and a slight decrease in pulmonary pressures with carvedilol. Accordingly, when the therapy is started, the most frequent adverse effects are worsening heart failure with metoprolol and bisoprolol, and hypotension and dizziness with carvedilol. It remains controversial whether these differences also influence the long term effects of therapy. Carvedilol may provide a more comprehensive blockade of the cardiac adrenergic drive than selective beta-blockers because it does not upregulate beta(1)-adrenergic receptors, blocks all adrenergic receptors and decreases cardiac norepinephrine release. These properties may lead to a larger increase in left ventricular function and a lack of improvement in maximal exercise capacity with carvedilol, compared with selective beta-blockers. It is, however, unclear whether these differences also influence patient outcome. The long term effects of different beta-blockers on prognosis are currently being compared in the Carvedilol or Metoprolol European Trial (COMET) in which more than 3000 patients with chronic heart failure have been randomized in a 1 : 1 ratio to receive metoprolol or carvedilol.
Adrenergic alpha-1 Receptor Antagonists↗
[Role of inflammation mediators in the pathogenesis of heart failure].
A number of factors are involved in congestive heart failure pathogenesis. Among these, inflammatory mediators could have a crucial role. Patients with congestive heart failure show increased plasma levels of "proinflammatory cytokines", in particular tumor necrosis factor-alpha and interleukin-6. Clinical and experimental models have demonstrated that these cytokines induce left ventricular dysfunction, pulmonary edema, ventricular remodeling, skeletal muscle abnormalities, myocyte apoptosis and endothelial dysfunction, suggesting the possibility that increased plasma concentration of cytokines could not be just an epiphenomenon, but an effective pathogenetic mechanism of disease progression. Additional inflammatory proteins involved in the acute phase response could play a part in the pathogenesis of heart failure. Pentraxin 3 is a prototypical long pentraxin, structurally related, although with different functions, to C-reactive protein, is produced by immune system cells, fibroblasts and particularly by cardiac endothelial cells and myocytes, as demonstrated in murine and human models. Its synthesis is rapidly induced after exposition to bacterial lipopolysaccharide and proinflammatory cytokines, as interleukin-1beta and tumor necrosis factor-alpha. In heart diseases, pentraxin 3 could be involved in the acute local inflammatory response to myocardial injury (e.g. necrosis) and in heart failure pathogenetic mechanisms, but its exact role is not yet settled. Defining the specific part played by these molecules in the pathogenesis of heart failure could lead to new therapeutic approaches in the treatment of cardiac insufficiency.
Cytokines↗
Differential effects of beta-blockers in patients with heart failure: A prospective, randomized, double-blind comparison of the long-term effects of metoprolol versus carvedilol.
BACKGROUND: Both metoprolol and carvedilol produce hemodynamic and clinical benefits in patients with chronic heart failure; carvedilol exerts greater antiadrenergic effects than metoprolol, but it is unknown whether this pharmacological difference results in hemodynamic and clinical differences between the 2 drugs. METHODS AND RESULTS: We randomized 150 patients with heart failure (left ventricular ejection fraction </=0.35) to double-blind treatment with either metoprolol or carvedilol. When compared with metoprolol (124+/-55 mg/d), patients treated with carvedilol (49+/-18 mg/d) showed larger increases in left ventricular ejection fraction at rest (+10.9+/-11.0 versus +7.2+/-7.7 U, P=0.038) and in left ventricular stroke volume and stroke work during exercise (both P<0. 05) after 13 to 15 months of treatment. In addition, carvedilol produced greater decreases in mean pulmonary artery pressure and pulmonary wedge pressure, both at rest and during exercise, than metoprolol (all P<0.05). In contrast, the metoprolol group showed greater increases in maximal exercise capacity than the carvedilol group (P=0.035), but the 2 drugs improved symptoms, submaximal exercise tolerance, and quality of life to a similar degree. After a mean of 23+/-11 months of follow-up, 21 patients in the metoprolol group and 17 patients in the carvedilol group died or underwent urgent transplantation. CONCLUSIONS: The present study demonstrates that during long-term therapy, carvedilol improves cardiac performance to a greater extent than metoprolol when administered to patients with heart failure in the doses shown to be effective in clinical trials. These differences were likely related to a greater antiadrenergic activity of carvedilol.
Adrenergic beta-Antagonists↗
Selective or nonselective beta-adrenergic blockade in patients with congestive heart failure.
Controlled clinical trials, performed in more than 13,000 patients, have consistently shown the beneficial effects of long-term beta-blocker therapy in patients with chronic heart failure. However, it is not clear whether this is a class effect or if it is specific only for some agents. Beneficial effects on the prognosis of the patients with mild to moderate heart failure have been obtained with metoprolol, bisoprolol, and carvedilol. Metoprolol and bisoprolol are selective for beta(1)-receptors and without ancillary properties, carvedilol, at doses of 25 mg twice daily, blocks beta(1)-, beta(2)-, and a(1)-adrenergic receptors, and has associated antiproliferative and antioxidant activities. These differences are important for the acute hemodynamic effects, but it is still controversial whether they may also influence the long-term effects of therapy. Differently from selective b-blockers, carvedilol blocks all adrenergic receptors, does not upregulate beta1-receptors, decreases cardiac norepinephrine release, and has associated antioxidant effects. These differences may cause a larger increase in left ventricular function, which was significant in some, but not all of the direct comparisons of the two agents. The long-term effects of different beta-blockers on prognosis are currently compared in the Carvedilol or Metoprolol European Trial, in which more than 3000 patients with chronic heart failure have been 1:1 randomized to metoprolol or carvedilol and are going to be followed for more than 2 years.
Adrenergic beta-Antagonists↗
A rationale for the use of beta-blockers as standard treatment for heart failure.
BACKGROUND: Cardiac sympathetic activation is one of the major and earlier changes observed in patients with heart failure. Its relation to the severity of the disease and its independent prognostic value show that it may directly contribute to the progression of heart failure. beta-Blockers are the most effective tool to counteract the untoward effects of sympathetic activation on the cardiovascular system. METHODS AND RESULTS: We reviewed the results of the placebo-controlled, double-blind studies about the effects of beta-blockers in patients with heart failure. These studies have involved almost 10,000 patients to date and have consistently shown that the long-term administration of beta-blockers is associated with a highly significant improvement in both left ventricular function and prognosis of the patients with heart failure. The evidence supporting the use of beta-blockers now equals or even surpasses that of angiotensin-converting enzyme inhibitors; therefore beta-blockers should be considered part of standard therapy. Issues that remain unclarified include the mechanisms through which beta-blockers may improve cardiac function and their tolerability and efficacy in specific groups of patients (such as those with asymptomatic left ventricular dysfunction, severe heart failure, the elderly, or those with left ventricular diastolic dysfunction). It is not currently clear whether the pharmacologic differences between individual beta-blockers are clinically relevant. If they are, the potential for even greater benefit with certain agents exists. It is hoped that these issues will be clarified by the results of ongoing multicenter trials.
Adrenergic beta-Antagonists↗
Use of cardiopulmonary exercise testing with hemodynamic monitoring in the prognostic assessment of ambulatory patients with chronic heart failure.
OBJECTIVES: We studied whether direct assessment of the hemodynamic response to exercise could improve the prognostic evaluation of patients with heart failure (HF) and identify those in whom the main cause of the reduced functional capacity is related to extracardiac factors. BACKGROUND: Peak exercise oxygen consumption (VO2) is one of the main prognostic variables in patients with HF, but it is influenced also by many extracardiac factors. METHODS: Bicycle cardiopulmonary exercise testing with hemodynamic monitoring was performed, in addition to clinical evaluation and radionuclide ventriculography, in 219 consecutive patients with chronic HF (left ventricular ejection fraction, 22 +/- 7%; peak VO2, 14.2 +/- 4.4 ml/kg/min). RESULTS: During a follow-up of 19 +/- 25 months, 32 patients died and 6 underwent urgent transplantation with a 71% cumulative major event-free 2-year survival. Peak exercise stroke work index (SWI) was the most powerful prognostic variable selected by Cox multivariate analysis, followed by serum sodium and left ventricular ejection fraction, for one-year survival, and peak VO2 and serum sodium for two-year survival. Two-year survival was 54% in the patients with peak exercise SWI < or = 30 g x m/m2 versus 91% in those with a SWI >30 g x m/m2 (p < 0.0001). A significant percentage of patients (41%) had a normal cardiac output response to exercise with an excellent two-year survival (87% vs. 58% in the others) despite a relatively low peak VO2 (15.1 +/- 4.7 ml/kg/min). CONCLUSIONS: Direct assessment of exercise hemodynamics in patients with HF provides additive independent prognostic information, compared to traditional noninvasive data.
Adult↗
[ACE-inhibitors, AT1 receptor antagonists and diastolic dysfunction].
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Angiotensin Receptor Antagonists↗
Maximal and submaximal exercise testing in heart failure.
Although reduced exercise capacity is the main complaint of patients with congestive heart failure (CHF), the best method to measure it remains controversial. Peak VO2, obtained using maximal exercise testing, is the most accurate measure of maximal functional capacity. It is related to peak exercise cardiac output and is one of the most important independent variables for the prognostic assessment of patients with CHF. It has, however, a low sensitivity for measurement of changes induced by therapy and is poorly related to everyday physical activity, patient symptoms, and quality of life. The anerobic threshold may also be regarded as a parameter of maximal functional capacity. Its value is mainly indirect, because it shows that the patient is performing a maximal effort limited by the cardiovascular system. The VO2 kinetics at the start and at the end of exercise are probably more related to patient symptoms, but it is unresolved which protocols and parameters might best be used to study this aspect of exercise performance. Duration of a submaximal exercise at a constant work rate and the distance walked during a 6-min walking test are gaining wide popularity as parameters of submaximal performance. However, when these exams are carried out up to exhaustion in patients with severe functional limitation, they may involve attainment of the anerobic threshold and therefore their clinical meaning may be similar to the one of a maximal exercise test. Moreover, tests based on the assessment of submaximal exercise capacity have been useful for assessment of therapy in single-center trials but have been often inadequate in multicenter trials.
Anaerobic Threshold↗
Effects of neurohormonal antagonism on symptoms and quality-of-life in heart failure.
Increased mortality and reduced functional capacity are the two main characteristics of chronic heart failure. Activation of the renin-angiotensin and sympathetic systems has a primary role in the progressive worsening of heart failure and increased mortality of patients. In addition, both systems may be important in the pathogenesis of exercise intolerance, although there is only a weak relationship between neurohormonal activation and exercise capacity. While neurohormonal antagonists, such as angiotensin-converting enzyme (ACE) inhibitors and beta-blockers, consistently improve the prognosis of patients with heart failure, their effects on exercise tolerance have often been less significant. This problem has been emphasized by the introduction of beta-blockers for the therapy of heart failure. Beta blockade results in a significant improvement in left ventricular function during rest and exercise. However, the reduction in chronotropic response to exercise as well as the metabolic changes caused by these agents in skeletal muscle may result in an apparent lack of change in maximal functional capacity. This effect is particularly important with the new third generation non-selective beta-blockers. The pronounced anti-adrenergic activity of these compounds accounts for their greater negative chronotropic effect and relates to the lack of improvement in peak oxygen consumption (VO2). Submaximal exercise testing can be used to assess changes induced by these agents. However, even the six-minute walk test may act as an almost maximal test in patients with advanced heart failure: moreover, the measurement of submaximal exercise duration may be sensitive enough to detect changes in single-centre trials, but not in multicentre trials. To date, direct assessment of symptoms by both patient and physician is still the most sensitive tool to monitor changes in functional status with non-selective beta-blockers. Thus, an accurate method of measuring patients' symptoms, in addition to the clinical examination, is still necessary when neurohormonal antagonists are used in patients with chronic heart failure.
Adrenergic beta-Antagonists↗
[Etiopathogenesis of acute myocardial infarction: role of early leukocytosis].
It has recently been suggested that inflammation may play an important role in the pathogenesis of acute ischemic syndromes. It may therefore be important to relate their clinical features with plasma indexes of inflammation. We have studied leukocyte, platelet and fibrinogen blood levels in 57 consecutive patients with acute myocardial infarction admitted to our Intensive Care Unit within 90 min after the onset of chest pain and treated with primary coronary angioplasty. Patients were divided into two groups on the basis of blood leukocyte levels: Group A, 24 patients, 17 males, mean age 54.2 +/- 13.7 years, with high blood leukocytes and Group B, 33 patients, 28 males, mean age 60.9 +/- 10.3 years, with normal blood leukocytes. Group A patients also had higher serum fibrinogen (p = 0.05) and blood platelet levels (p < 0.05). The stenosis observed after guidewire advancement was significant (> 75%) in 33% of the patients with leukocytosis vs 94% of the others (p < 0.01). No difference between the two groups was observed in the success rate of coronary angioplasty and prevalence of stent placement (100 vs 97%, and 43 vs 42% of the patients of Group A and B, respectively). In contrast, a tendency to rethrombosis requiring Rheopro administration was observed in 62% Group A patients vs 21% Group B patients (p < 0.01). In conclusion, the finding of leukocytosis in the acute phase of myocardial infarction suggests that coronary occlusion is mainly caused by a coronary thrombus occurring at the site of a non significant stenosis. In contrast, when blood leukocytes are normal, the underlying coronary stenosis is more often critical and the thrombotic process is less important. The high blood leukocytes, platelet and fibrinogen levels of Group A patients are consistent with a significant role of inflammation in the pathogenesis of the thrombotic process while hemodynamic and local mechanical factors are probably more important in patients with normal blood leukocytes.
Adult↗
[The effects of mid- and long-term administration (3-4 years) of carvedilol in patients with idiopathic dilated cardiomyopathy].
Carvedilol has been shown to determine a significant improvement in left ventricular function, symptoms, clinical course and prognosis of patients with chronic heart failure. However, these results were obtained in medium-term studies of < 1 year duration. We report the results obtained with long-term (3-4 years) carvedilol administration to 40 patients with idiopathic dilated cardiomyopathy who were initially recruited in a 4-month double-blind placebo-controlled trial. In the initial 4-month double-blind trial, 20 patients were randomized to placebo and 20 to carvedilol treatment. All patients, except one who was not on ACE-inhibitors, were on digoxin, furosemide and ACE-inhibitors. Carvedilol or placebo doses were progressively titrated, at weekly intervals, up to the maximal doses of 25 mg bid. After the initial 4-month double-blind phase, all patients were followed long term. Mean follow-up duration was 52 +/- 12 months (range 48-61). Among the 20 patients initially randomized to carvedilol administration, 4 died (3 for cardiac and 1 for extracardiac causes) and 2 underwent heart transplant. Among the 20 patients initially randomized to placebo, 5 died for cardiac causes, 3 underwent heart transplant and 4 were started on carvedilol because of progressive heart failure during the initial 4 months of the study. The remaining 8 patients, who were kept on digoxin, furosemide and ACE-inhibitors, were used as control group. Each patient underwent an assessment of clinical conditions (NYHA functional classification and Minnesota Living with Heart Failure questionnaire), equilibrium radionuclide ventriculography, and maximal cardiopulmonary bicycle exercise testing. Exams were performed before treatment, after 4 and 12 months, and at the end of the follow-up period. No significant difference between the carvedilol and control group was present at baseline. Compared with baseline, patients in the control group presented a significant increase in left ventricular end-diastolic volume after long-term follow-up (from 126 +/- 62 to 138 +/- 43 and 158 +/- 52 ml/m2 after 12 and 48 months, respectively). No significant difference, compared to baseline values, was noted. Patients on carvedilol presented a persistent improvement in left ventricular function. This was shown by the progressive increment in left ventricular ejection fraction from 22 +/- 6 to 34 +/- 11, 37 +/- 11 and 37 +/- 13%, after 4, 12 and 48 months, respectively (p < 0.001) with a concomitant reduction in left ventricular end-diastolic volume from 147 +/- 54 to 101 +/- 44 ml/m2 at the end of the follow-up (p < 0.05). NYHA functional class remained significantly improved, in comparison with baseline (2.6 +/- 0.5 to 1.9 +/- 0.3, 1.9 +/- 0.8 and 2.0 +/- 1.0 after 4, 12 and 48 months, respectively; p < 0.01). Maximal functional capacity, assessed as peak VO2 was not significantly changed after 4 months (from 15.2 +/- 3.6 to 16.4 +/- 4.0 ml/kg/min) and showed a tendency towards a further improvement after 12 months and at the end of the follow-up (17.3 +/- 5.6 and 17.2 +/- 5.3 ml/kg/min, respectively). These results show that the favorable effects of carvedilol administration on left ventricular function and clinical symptoms are maintained also after long-term treatment.
Adrenergic beta-Antagonists↗
Pharmacological activity of the new calcium antagonist, lacidipine, on isolated preparations.
1. The calcium-channel blocking activity of lacidipine has been studied compared with that of nifedipine and verapamil on the isolated rabbit heart and aorta. 2. All the compounds induced a dose-dependent negative inotropic effect (10(-8)-10(-5) M); although lacidipine showed less, but longer lasting, activity. 3. Lacidipine showed a weak negative chronotropic effect and nifedipine was ineffective. Only verapamil strongly decreased the heart rate. 4. The three calcium antagonists abolished vasopressin-induced coronary spasm and inhibited partially metoxamine-induced coronary spasm. Only lacidipine reduced basal coronary pressure. 5. In the aortic strips, all the compounds antagonized KCl-induced contractions, and they exerted a partial effect on noradrenaline- and angiotensin II-induced contractions.
Animals↗
[Clinical efficacy of oral dopaminergic agents: new findings].
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Administration, Oral↗
[Current role of non-digitalis inotropic agents in acute and chronic treatment of heart failure].
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Acute Disease↗
[Stress and ischemic heart disease].
The role of mental stress in ischemic heart disease is two-fold: as a risk factor of coronary artery disease and as a trigger of acute ischemic attacks in patients with established coronary atherosclerosis. The role of stress as a risk factor is still controversial. Data regarding the relationship between occupational factors and development of coronary atherosclerosis have not been confirmed. A type personality, above all when anger and hostility traits are present, seems to be a predisposing factor for the development of coronary artery disease. These data however, were not confirmed in study groups including patients with a higher prevalence of other, more important, risk factors. Stress can have an important role as a trigger of acute ischemic attacks. This is indirectly shown by the circadian distribution of the main manifestations of ischemic heart disease (sudden death, myocardial infarct, ST segment depression). In fact, their incidence is significantly higher in the morning hours, after awakening, when mental stress is higher. In the laboratory setting, mental stress can induce myocardial ischemia in a variable percentage of patients (0 to 80%). Prevalence of mental stress-induced myocardial ischemia varies depending on the stressor used, the patients group and, above all, the diagnostic tool. Ischemic episodes induced by mental stress, in fact, are generally silent and less severe and extensive than those elicited by exercise stress testing. It is therefore often necessary to use methods, such as myocardial scintigraphy, with higher sensitivity for the detection of myocardial ischemia in comparison with ECG. Patients with mental stress-induced myocardial ischemia tend to present higher scores on measures of aggressivity, anger and hostility. These psychological features are related to a hightened cardiovascular reactivity with a brisk and greater increase in heart rate and blood pressure after exposure to stress. It would be therefore useful to identify patients with such a behaviour by psychological assessment and/or analysis of sympatho-vagal balance by analysis of heart rate variability. The mechanism by which mental stress can induce myocardial ischemia is represented by an increase in myocardial oxygen demand, through the increased heart rate and blood pressure, probably associated with an increase in coronary vascular resistance. This last phenomenon is likely caused by small coronary vessel constriction mediated by alpha-adrenergic activation and by a reduced EDRF release by the damaged endothelium.
Acute Disease↗
[Interaction between electrolytes and the neurohumoral system. The clinico-prognostic implications of hyponatremia, hypopotassemia and hypomagnesemia in congestive heart failure].
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Combined Modality Therapy↗