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Unlabelled: Severe sepsis and septic shock have a mortality rate that may range between 28 and 50%. It is estimated that approximately 200,000 patients die per annum in the USA as a consequence of sepsis. The reduction of plasma endotoxin levels to achieve a favourable outcome for septic patients has been previously demonstrated but the effectiveness of treatments targeting single inflammatory mediators during established sepsis has been disappointing. Furthermore,some clinical study clinically showed valuable reduction in cytokine levels by hemofiltration alone. The prompt removal of endotoxins could be an effective way to reduce the immunological activation and the amount of NO produced by endotoxin-activated inducible NO-synthase in many tissues and cells. The polymyxin B cartridge is an extracorporeal hemoperfusion device (PMX-DHP) known to remove circulating endotoxins. Open-label clinical trials testing PMX-DHP have demonstrated its safety in the septic shock treatment while the overall survival rate significantly improved in comparison with the control groups. The purpose of this study was to investigate the effects of PMX-DHP on redox status, inflammatory cytokine profile, monocytes and PMN leukocyte activation in Gram-negative sepsis. Prospective study: six patients, 2 males and 4 females 60.5+/-24.5 years old, in ICU for severe Gram-negative sepsis (emergency surgery for intra abdominal infection). Two PMX-DHP runs, at T0 and T1; 2 hours each; the first within 24 hours from sepsis diagnosis or 12 hours after emergency surgery, the first PMX-DHP at T0, the second after 24 hours.; APACHE II score at T0: 20.1+/-3.7; SOFA score 14.2+/-2.5; organ failure: 3+/-1.5; norepinephrine(Ne) in 1 patient; Ne + dopamine (DA) in 4 patients; DA in 1 patient only. Mean dosage: Ne 0.24 mcg/kg/min; DA 8.9 mcg/kg/min. Four patients in CRRT (continuous veno-venous hemofiltration, AN69 hemofilter) for the entire length of the study. QB 100+/-10 ml/min. Pre and post PMX-DHP, plasma endotoxins as well as anti-IL 1-beta, IL2, IL4, IL5, IL6, IL8, IL10, TNF-alpha, GM-CSF, IFN-gamma levels were measured. Expression of CD64 on monocytes and PMN leukocytes and I -2r CD25 on CD4+ T cells by flow cytometry. Total and reduced plasma cysteine, homocysteine, glutathione (GSH); plasma glutathione peroxidase (GSH-Px) and reductase (GSH-Rx); erythrocyte GSH (eGSH), eGSH-Px and eGSH-Rx; NADP and NADPH and their ratio assessed pre and post PMX-DHP, all compared with 15 age and gender-matched healthy subjects for complete REDOX characterization., Results: We observed a significant reduction of endotoxin levels post PMX-DHP; CD64 monocytes and PMN leukocytes overexpression returned to normal; pro-inflammatory cytokines Il6, Il 10 and TNF-alpha were significantly reduced. We detected no differences in plasma levels of anti-IL 1-beta, IL2, IL4, IL5, IL8, GM-CSF, IFN-gamma pre versus post PMX-DHP. SOFA score from 14.2+/-2.5 to 8.9+/-2.1 post PMX-DHP runs. Four out of six patients survived and were discharged; mortality was 33% versus the anticipated 51%., Conclusion: PMX-DHP reduces circulating endotoxins, down-activates monocytes and PMN leukocytes, reduces pro-Inflammatory cytokines and corrects the redox environment imbalance preventing oxidative damage to endothelial cells and the metabolic and functional microvascular derangements that usually lead to multi-organ failure and septic shock.

Central to the pathophysiology of sepsis and septic shock is an alteration in endothelial cell function and oxidative stress. Highly complex, integrated responses that include the activation of a number of cell types, inflammatory mediators and the hemostatic system are involved in endothelial dysfunction. On the other hand, the imbalance between the excessive production of reactive oxygen species and/or inadequate antioxidative defenses characterizes the oxidative stress. The overview of all these mechanisms suggests clinical biochemical markers as a possible therapeutic target together with correct intervention timing.

Common complications after heart transplantation include acute rejection and coronary allograft vasculopathy. In order to detect the presence of rejection, tissue Doppler imaging echocardiography provides high accuracy and allows to optimize the timing of endomyocardial biopsies, which remain the cornerstone in rejection diagnosis. Coronary allograft vasculopathy is often a diffuse disease so that it is difficult to recognize by imaging modalities, such as myocardial perfusion scintigraphy, which are based on intra-patient comparison of different areas. Quantitative assessment of the myocardial blood flow by positron emission tomography overcomes this issue. Dobutamine stress echocardiography provides accurate diagnosis as well as useful prognostic information. Nevertheless, intracoronary ultrasound is nowadays considered the gold standard for vasculopathy assessment, since it is able to detect a minimum intimal thickening which represents the early feature of disease. Magnetic resonance represents the most attractive approach, though it has not yet gained widespread clinical use.

The mechanisms regulating coronary collateral circulation are largely unknown owing to both the complex and variable nature of clinical models and the difficulty to obtain quantitative and differentiated flow measurements within the various coronary tree portions. With the aim of assessing collateral flow reserve, we studied 19 patients with effort angina, without myocardial infarction and with isolated occlusion of either the left anterior descending coronary artery (n = 14) or the circumflex coronary artery (n = 5). Flow values were measured basally, during atrial pacing induced tachycardia and following ev dipyridamole infusion (0.56 mg/kg of body weight in 4 min), by means of positron emission tomography and nitrogen-13 ammonia as flow tracer, within both regions depending on collateral circulation and the remote ones. Results have been compared with those obtained in 13 normal subjects. Basal flow values in regions depending on collateral circulation and in the remote regions (0.61 +/- 0.11 vs 0.63 +/- 0.17 ml/min/g) were found to be similar, but lower than in normal subjects (1.00 +/- 0.20 ml/min/g, p < 0.01). During atrial pacing, flow increased to 0.83 +/- 0.25 and to 1.11 +/- 0.39 ml/min/g, in the regions depending on collateral circulation and in the remote regions, respectively (p < 0.05 as compared to baseline); again, values were lower than in normal subjects (1.86 +/- 0.61 ml/min/g, p < 0.01). Dipyridamole infusion further increased flow in the remote regions (1.36 +/- 0.57 ml/min/g, p < 0.01 as compared to atrial pacing) but it did not in the regions depending on collateral circulation (0.94 +/- 0.37 ml/min/g, NS as compared to atrial pacing); both values were lower than in normal subjects (3.46 +/- 0.78 ml/min/g, p < 0.01). Flow reserve in the regions depending on collateral circulation was found to have a direct linear correlation with the one in the remote regions (r = 0.83; p < 0.01). In conclusion, in spite of basal hypoperfusion, collateral circulation maintains a flow reserve which, even if reduced, is able to cope with moderate increments in oxygen consumption. An analogous flow reduction can be observed in the remote regions, suggesting that the entire coronary tree is involved, beyond the obstructive lesions of the main arterial branches.

Background: The natural history of idiopathic dilated cardiomyopathy (IDC), once a disease with a dire prognosis, is thought to be changing. Aim of this study was to describe the clinical characteristics, long term course and prognostic factors of IDC patients followed up prospectively since the late eighties., Methods: Patients with a diagnosis of IDC confirmed by normal coronary angiography, non specific endomyocardial biopsy findings and a left ventricular ejection fraction below 50% were consecutively enrolled in a multicenter registry and followed up at 6-months intervals., Results: From January 1986 till January 1994, 441 IDC patients with a mean age of 43 +/- 13 years (range 8-68) entered the registry. Thirty per cent of patients were women and 8% had familial dilated cardiomyopathy. NYHA class was I-II in 77% and 35% of patients were asymptomatic at the time of diagnosis. Treatment included digitalis in 235 patients (53%), diuretics in 239 (54%), angiotensin converting enzyme inhibitors in 269 (61%), betablockers in 108 (24%). Chronic atrial fibrillation was detected in 10% of patients and left bundle branch block in 24%. Mean cardiothoracic ratio was 0.54 +/- 0.06. Mean left ventricular end diastolic dimension was 38 +/- 6 mm/m2; 48% of patients had minimal or mild left ventricular dilatation. Mean left ventricular ejection fraction was 30 +/- 10%. At Holter monitoring 67% of cases had complex ventricular arrhythmias, 37% had ventricular tachycardia and 4% had advanced atrioventricular block. Mean exercise stress test duration was 9 +/- 4 minutes. After a mean follow up of 31 +/- 24 months, 337 patients were alive without transplantation and 5 were lost to follow up; 60 patients (14%) had died of cardiac causes, namely heart failure (6%), sudden death (7%) and pulmonary embolism (< 1%) and 30 had been transplanted (7%), while 4 had died of unclear causes. Survival and transplant-free survival were 94% and 90% at 2 years and 82 and 76% at 5 years, respectively. At multivariate analysis pulmonary capillary wedge pressure (p = 0.0001, odds ratio, for values > 15 mm Hg, 2.05) and betablocker treatment (p = 0.002, odds ratio 0.26) were independent predictors of survival., Conclusions: In this large, multicenter prospective study, prognosis of IDC in the eighties appears to be improved. Early diagnosis, together with improved medical treatment, probably bears a causal relation to these changes.

Aim of the Study: Aim of this study is to investigate whether, in patients with coronary artery disease (CAD), regional myocardial blood flow (rMBF) regulation is affected with further mechanisms besides the effects of epicardial coronary stenosis., Material and Methods: RMBF and coronary reserve are measured in 13 normal subjects and in 36 patients with effort angina and isolated (> or = 50% diameter narrowing) left anterior descending (LAD, 27 patients) or left circumflex (LCX, 9 patients) coronary artery stenosis. Measurements are obtained both at baseline and following dipyridamole (0.56 mg/kg in 4 minutes) using positron emission tomography and N13-ammonia., Results: At rest, patients with CAD show similar rMBF values in the stenotic and remote areas (0.71 +/- 0.19 vs 0.77 +/- 0.22 ml/min/gr, respectively, ns); both values are significantly (p < 0.01) reduced with respect to mean rMBF observed in the normal subjects (1.07 +/- 0.21 ml/min/gr). Following dipyridamole, patients with CAD show lower rMBF values in stenotic than in control regions (1.25 +/- 0.54 vs 1.73 +/- 0.80 ml/min/gr, p < 0.01); however, both these values are significantly reduced when compared with mean rMBF in the normal subjects (3.76 +/- 0.88 ml/min/gr, p < 0.01). To evaluate whether reduction in resting myocardial perfusion indicates maximal vasodilatation, patients with CAD are divided into 2 groups: Group 1 with homogeneous baseline perfusion (0.73 +/- 0.2 vs 0.75 +/- 0.24 ml/min/gr, in stenotic and remote areas, respectively, ns), and Group 2 with baseline perfusion defect in the stenotic related territory (0.62 +/- 0.14 vs 0.84 +/- 0.17 ml/min/gr, p < 0.01). Coronary reserve (dipyridamole flow/baseline flow) is similar in the 2 Groups (1.74 +/- 0.66 vs 1.93 +/- 0.45, ns)., Conclusions: These data suggest that, in patients with CAD, other factors beyond hydraulic effects of epicardial coronary stenosis, could modulate rMBF regulation; in fact: 1) myocardium perfused by angiographically normal coronary artery shows reduced values of both resting rMBF and coronary reserve; 2) myocardium supplied by stenotic vessel maintains a residual vasodilating capability despite a reduced baseline perfusion.

We studied the hemodynamic effects of dobutamine in 10 patients with severe chronic heart failure due to congestive cardiomyopathy in 5, to ischemic heart disease in 4 and to hypertensive cardiomyopathy in 1. Dobutamine was injected during three periods of 30 min each alternated with equal periods of placebo at doses of 2,5-5 and 7,5 mcg/Kg/min respectively. The most favorable hemodynamic effects, obtained at an infusion rate of 5 mcg/Kg/min, was characterized by a significant inn 4 and to hypertensive cardiomyopathy in 1. Dobutamine was injected during three periods of 30 min each alternated with equal periods of placebo at doses of 2,5-5 and 7,5 mcg/Kg/min respectively. The most favorable hemodynamic effects, obtained at an infusion rate of 5 mcg/Kg/min, was characterized by a significant increase of the cardiac index and of the left ventricle stroke work index, accompanied by a significant decrease of the left ventricular filling pressure and of the systemic and pulmonary vascular resistance. The hemodynamic monitoring showed that the pharmacological effects of the drug subsided about 5-10 min after the interruption of infusion. At the infusion rate of 7,5 mcg/Kg/min we observed a significant increase of premature ventricular beats in 3 patients. We conclude that dobutamine at the dose of 5 mcg/Kg/min shows a powerfull positive inotropic action not accompanied by apparent side effects.

The study of 46 patients with frequent anginal episodes characterized by S-T elevation (so called "variant angina pectoris") demonstrated that this type of electrocardiographic pattern does not characterize a homogeneous group of patients. In fact, while in some patients angina occurred only at rest, in others it occurred also on exercise. Sometimes ecgraphic alterations characterized by S-T depression were observed on the same leads which on other occasions had shown S-T elevation. The angiographic picture revealed: absence of significant coronary alterations in 10% of cases, stenosis greater than 75% in one main branch in 29%, in two branches in 39% and in three branches in 22% of cases. The hemodynamic monitoring carried out on 14 of these patients demonstrated that the ecgraphic modifications occur before the onset of the hemodynamic parameters which control myocardial O2 consumption. This suggests a primitive reduction of regional myocardial blood supply as a cause of the ischaemic episodes. The study of the regional myocardial perfusion with 201Tl technique in 6 patients confirmed this hypothesis. Coronary angiography carried out during an ischemic episode showed that the reduction of myocardial blood supply was caused by a spasm of a large coronary artery involving a long segment of the vessel, reversible by nitroglycerin administration. Aorto-coronary by-pass operation performed on 6 patients was followed by the disappearance of pain in two patients, even though the "by-pass" patency was angiographically proved in two patients.

Purpose of this study was to evaluate the capability of M-mode echocardiography (M-mode) and of 201Thallium myocardial scintigraphy (201T1) to detect transient myocardial ischemia at rest in man. Fourteen male patients (pts) were studied by the two techniques under basal conditions and during episodes of angina at rest. Data were obtained in 2 pts in rapid succession during the same episode, in the remaining 12 pts in different episodes with electrocardiographic changes similar in site, type, entity and duration. Echocardiographic criteria of transient ischemia (reversible asynergies and transient reduction of systolic thickening) were present in 9/11 pts during episodes of ST segment elevation; the scintigraphic ones (reversible perfusion defects) in 10/11 pts. In 3 pts during episodes of ST segment depression M-mode was positive in 2, 201T1 in all three. The poor acoustic window in 2 pts and the involvement in one of left ventricular lateral wall not seen by M-mode on parasternal approach, may account for the 3 false negatives of M-mode. The single false negative of 201T1 can be related to the short duration (1') of the episode. A complete correspondence of site of ischemia, detected by ECG, M-mode and T1, was observed. In conclusion, M-mode appears a reliable technique for detecting transient ischemic episodes, being the main limits the acoustic window and the incapacity in exploring all ventricular walls and the main advantage the high temporal resolution, which permits to study continuously the full sequence of the ischemic event. On the other hand 201T1 does not allow detection of episodes of short duration. This two techniques, when combined in anginal patients, provide complementary information on perfusion and contraction respectively. The reliability of these techniques in the assessment of transient myocardial ischemia is the basis for their possible diagnostic use in pts with transient specific ECG changes or with typical anginal pain without ECG evidence of ischemia.

Radiolabeled human albumin microspheres (HAM) have been used in the past, in order to visualize coronary flow distribution in man. In order to obtain information both on myocardial perfusion and contractility, we applied R-wave synchronized reconstruction of the cardiac cycle in cine mode to HAM imaging. In 20 patients with angina pectoris and coronary stenosis of variable severity and in 1 patient with congestive cardiomyopathy we injected 4 millions of HAM (mean diameter 15 microns) labeled with 15-20 mCi of 99mTc, into the left ventricle during routine cardiac catheterization. Data were collected by a gamma camera, and by the use of a high resolution collimator and were electronically restricted to the cardiac area (64 X 64 matrix). The reconstruction of the cardiac cycle was made according to the technique developed in our laboratory for gated blood pool imaging. From the displayed images we evaluated myocardial flow distribution at the time of injection and regional wall motion (by cine mode) at any subsequent time, with a temporal resolution of 2 to 4 mins. The patterns of contractility of myocardial walls with normal or reduced perfusion were in agreement with those observed by means of contrast ventriculography. Advantages of the technique are: a) simultaneous information on flow and contractility; b) prolonged time for wall motion observation (4 to 6 hours); c) high quality pictures, since the signal to background ratio is much more favourable than with other isotope techniques. The technique appears to be promising from the results obtained in the number of patients included in this study.

In ischemic heart disease, the left ventricle has been considered the main target of an imbalance between myocardial oxygen supply and demand. Accordingly, the approach to ischemia has been directed at the evaluation of the left ventricle. The aim of this study was to assess the relative involvement of the left and right ventricle in patients with isolated right coronary artery stenosis. We studied 20 patients with a clinical history of effort angina (15 male, 5 female, mean age 54.1 +/- 6.2) using radionuclide angiography and atrial pacing. Findings were compared with those of 6 normal subjects that were paced at the maximal heart rate of 150 beats/min. Atrial pacing was interrupted because of diagnostic ST segment depression in 8 patients, Wenckebach type atrioventricular block in 1, chest pain without electrocardiographic changes in 4 and the achievement of the maximal prefixed heart rate of 150 beats/minute in 7. With respect to control conditions, during atrial pacing right ventricular ejection fraction declined from 46.8 +/- 6.8% to 37.4 +/- 8.1% (p less than 0.001), while no significant change was observed in left ventricular ejection fraction values (55.2 +/- 4.5% and 51.1 +/- 10.2% respectively). During atrial pacing, left ventricular peak filling rate increased from 1.77 +/- 0.53 to 4.71 +/- 1.8 end-diastolic volumes/second (p less than 0.0001). Qualitative analysis of regional wall motion showed a right ventricular dysfunction in 19/20 patients; this was prevalent in 9 and involving also the left ventricle in 10; an isolated impairment of the left ventricle was observed in 1 patient.(ABSTRACT TRUNCATED AT 250 WORDS)

Unlabelled: In the past ten years we studied 80 patients with angina at rest by 201-Thallium perfusion scintigraphy. According to ECG changes during episodes of transient ischemia at rest, the patients were divided into three groups. Thirty six patients showed transient ST segment elevation (Group 1); 33 ST segment depression (Group 2) and 11 normalization of negative T waves (Group 3). 201-TI scintigraphy was performed during spontaneous or ergonovine induced episodes of ischemia and at redistribution. Group 1 showed localized and severe perfusion defects, well correlated to the site of ECG changes. Group 2 showed more diffuse and less severe perfusion defects, less correlated to the site of ECG changes. Group 3 showed perfusion defects similar to those observed in Group 1 and associated in 54% with basal perfusion defects due to previous myocardial infarction., In Conclusion: A) three main perfusion patterns are associated with the three types of ECG changes; B) relative to ECG, myocardial scintigraphy provides a more accurate definition of the site and extension of ischemia, particularly in Group 2 patients.