Inhibition of tumor necrosis factor-alpha (TNF-alpha) production and arthritis in the rat by GW3333, a dual inhibitor of TNF-alpha-converting enzyme and matrix metalloproteinases.

Tumor necrosis factor-alpha (TNF)-converting enzyme (TACE) cleaves the precursor form of TNF, allowing the mature form to be secreted into the extracellular space. GW3333, a dual inhibitor of TACE and matrix metalloproteinases (MMPs), was compared with an anti-TNF antibody to evaluate the importance of soluble TNF and MMPs in rat models of arthritis. Oral administration of GW3333 completely blocked increases in plasma TNF after LPS for up to 12 h. In a model wherein intrapleural zymosan injection causes an increase in TNF in the pleural cavity, GW3333 completely inhibited the increase in TNF in the pleural cavity for 12 h. Under these dosing conditions, the plasma levels of unbound GW3333 were at least 50-fold above the IC(50) values for inhibition of individual MMPs in vitro. In a model wherein bacterial peptidoglycan polysaccharide polymers reactivate a local arthritis response in the ankle, a neutralizing anti-TNF antibody completely blocked the ankle swelling over the 3-day reactivation period. GW3333 administered b.i.d. over the same period also inhibited ankle swelling, with the highest dose of 80 mg/kg being slightly less active than the anti-TNF antibody. In a 21-day adjuvant arthritis model, the anti-TNF antibody did not inhibit the ankle swelling or the joint destruction, as assessed by histology or radiology. GW3333, however, showed inhibition of both ankle swelling and joint destruction. In conclusion, GW3333 is the first inhibitor with sufficient duration of action to chronically inhibit TACE and MMPs in the rat. The efficacy of GW3333 suggests that dual inhibitors of TACE and matrix metalloproteinases may prove therapeutic as antiarthritics.

Four cases of acute chagasic myocarditis in French Guiana.

The authors report four cases of acute chagasic myocarditis which had been diagnosed and treated in Cayenne, French Guiana, in the past 6 years. This French territory, which has the highest standard of living in South America, should be considered an area of risk for sporadic Chagas disease with epidemiologic features similar to those of the disease found in dense Amazon forest areas. Appropriate measures must be taken to screen and promptly manage Chagas disease in the French Guiana population.

[Prognostic factors in dilated cardiomyopathy]. / Etude des facteurs pronostiques des cardiomyopathies dilatées.

Thirty-eight patients, 27 men and 11 women, mean age 49 +/- 12 yr, suffering from dilated cardiomyopathy were included in this prospective study of prognostic factors. Twenty-two subjects admitted heavy alcohol consumption (greater than 80 g/d, for at least 10 yr). The survival rates for 2, 5 and 7 yr were 87, 35 and less than 20%, respectively. Prognostic factors were evaluated in 34 (22 alcoholic and 12 non-alcoholic) patients: 10 improved or were cured, as determined clinically, radiologically and echocardiographically (group 1); 24 deteriorated, 13 of whom died (group 2). Statistically significant values for group 1 versus group 2 were: echocardiographic left ventricular (LV) end diastolic diameter (3.50 +/- 0.80 vs 4.02 +/- 0.5 cm/m2, p less than 0.026) and LV end systolic diameter (2.97 +/- 0.65 vs 3.43 +/- 0.53 cm/m2, p less than 0.02); hemodynamic LV systolic pressure (113.9 +/- 15 vs 101.82 +/- 17.36 mm Hg, p = 0.045); angiographic LV end diastolic volume (137.8 +/- 57.44 vs 177.85 +/- 55.45 ml/m2, p = 0.057), LV end systolic volume 93 +/- 53.5 s 139.28 +/- 48.99 ml/m2, p less than or equal to 0.036), ejection fraction 0.36 +/- 0.16 vs 0.22 +/- 0.7%, p less than or equal to 0.006) and velocity of fiber shortening (0.79 +/- 0.53 vs 0.36 +/- 0.3 circ/s, p = 0.036). Other electrical, radiological and hemodynamic parameters were not significant and alcohol consumption did not influence the prognosis. The severity of LV functional impairment appears to be the major determinant of a poor prognosis and reduced survival in idiopathic and alcoholic cardiomyopathies.

[Study of dilated cardiomyopathies using gallium 67 myocardial scintigraphy]. / Exploration des myocardiopathies dilatées par la scintigraphie myocardique au gallium 67.

Twenty-seven patients were diagnosed as having dilated cardiomyopathies, based on increases in the cardiothoracic index greater than 0.50, in the diastolic and systolic diameters of the left ventricle, and in the telediastolic volume of the left ventricle, which was indexed by body surface determined by contrast ventriculography. They underwent gallium 67 scintigraphic examination of the myocardium, in order to non-invasively detect the presence of an inflammatory infiltrate. Fifteen of them also had endomyocardial biopsies and all had virology check-up. The results were disappointing. Only in one case was the scintigraphic image undeniably positive; in 20 other patients the findings were dubious or negative. This technique did not demonstrate the presence of an inflammatory infiltrate and thus we could not establish an association between myocarditis and dilated cardiomyopathy.

[Identification of prognostic criteria of dilated cardiomyopathies associated with chronic alcoholism. 22 cases]. / Contribution à l'identification des critères pronostiques des myocardiopathies dilatées associées à un alcoolisme chronique. 22 observations.

Between November, 1978 and August, 1983, 22 patients aged from 28 to 65 years with idiopathic dilated cardiomyopathy diagnosed on the basis of clinical and haemodynamic criteria were investigated. All these patients, who consumed alcohol in excessive amounts, were followed up for 1 to 58 months. The overall mortality rate was 10 p. 100 at 4 months and 25 p. 100 at 58 months. Six patients were clinically improved with reduction of heart size (group A); 10 patients showed deterioration with 3 deaths (group C) and 6 patients followed an intermediate course (group B). When the characteristics of the groups were evaluated, it was found that compared to group C patients those in groups A and B had a lower cardiothoracic ratio: 0.56 +/- 0.04 (B) vs 0.64 +/- 0.06 (C) (P less than 0.02), a lower indexed end-diastolic diameter and systolic diameter on TM echo: 3.20 +/- 0.50 cm/m2 (A) vs 4.13 +/- 0.39 cm/m2 (C) (P less than 0.02), and 2.72 +/- 0.37 cm/m2 (A) vs 3.57 +/- 0.47 cm/m2 (C) (P less than 0.02) respectively, and a lower indexed end-diastolic volume as evaluated by angiography: 121 +/- 61 ml/m2 (A) vs 202 +/- 65 ml/m2 (C) (P less than 0.06). Dilated cardiomyopathy associated with excessive alcohol consumption has a better prognosis when the patients stop drinking and when their heart dilatation is mild to moderate.

Assessment by dipyridamole-thallium-201 myocardial scintigraphy of coronary risk before peripheral vascular surgery.

From October 1983 to January 1985, 46 patients (38 men and 8 women; average age, 60 years; range, 37 to 83 years) underwent peripheral vascular surgery of either the internal carotid artery or the arteries of the lower limbs. Each patient had a thorough clinical examination, an ECG, and a dipyridamole-thallium-201 myocardial scan before operation. On the basis of results, they were divided into two groups: 20 patients with and 26 patients without chronic ischemic heart disease. Three major cardiac events were noted during or after a period of 1 month after surgery: There were two deaths due to cardiac ischemic events and one patient had postoperative unstable angina pectoris. These three patients were classified in the coronary group (NS). When the patients were classified on the basis of whether or not there was thallium redistribution on serial images after infusion of dipyridamole, 14 with redistribution and 32 without redistribution were noted. The three patients who had major cardiac events were in the former group (p less than 0.04). Our data suggest that patients in whom redistribution occurs have a high incidence of postoperative ischemic events. These patients should be considered for particular preoperative coronary care to avoid major postoperative cardiac events and to increase chances of survival.

[Subacute myocarditis as a manifestation of acquired immunodeficiency syndrome]. / Myocardite d'évolution subaiguë révélatrice d'un syndrome d'immuno-déficience acquise.

A case of acquired immunodeficiency syndrome associated with myocarditis is reported. The myocarditis was peculiar in that it heralded the syndrome and followed a subacute course. It was most probably of infectious origin, although no pathogen has positively been identified; it may have been caused by a cytomegalovirus or even by the human immunodeficiency virus itself on a background of genetic predisposition. This case shows that while cardiologists are concerned with cardiac disorders occurring during AIDS, they must also consider the possibility of AIDS when confronted with a myocarditis.

[Radiation-related atrioventricular block]. / Bloc auriculoventriculaire radique.

Twelve years after mediastinal irradiation for Hodgkin's disease, a 38-years old man developed an infra-hisian atrioventricular block with syncopes. The rarity of this complication of radiotherapy is emphasized. A review of the literature yielded only 6 cases of atrioventricular block associated with cobalt therapy; a pathological examination was performed in two of these patients and an electrophysiological study in two others.

[Tetralogy of Fallot in adults. Apropos of 43 cases with 38 total corrections]. / La tétralogie de Fallot chez l'adulte. A propos de 43 observations avec 38 corrections complètes.

The records of 43 patients older than 18 years presenting with tetralogy of Fallot were retrospectively examined to determine the semiological characteristics of the disease in adults. One or more palliative operations had previously been performed in 27 patients. Full correction was carried out in 38 patients with results described below. Tetralogy of Fallot has the following characteristics in adults as compared with children: clinically, heart failure, attacks of angina, haemoptysis and sequelae of previous complications are more frequent; at electrocardiography, right atrial hypertrophy, right bundle disorders of conduction and ventricular extrasystoles are also more frequent; radiology shows that cardiomegaly is no longer exceptional; haemodynamic studies demonstrate an increase in right atrial and right ventricular end-diastolic pressures. These characteristics indicate a deterioration of haemodynamic adjustment to the disease with age. The operative morbidity mostly consisted of haemorrhages (55% of the patients), more frequent in subjects with permeable anastomoses (p less than 0.01), and heart failure (50% of the patients) the frequency of which increased with the subject's age, the duration of the operation and the use of an infundibulo-pulmonary prosthesis (p less than 0.05). The operative mortality (18%) depended on the extent of the pulmonary stenosis and on the presence of a previous anastomosis (p = 0.04). An analysis of the causes of death reported in the literature showed that in adults the presence of an anastomosis constitutes a separate risk factor in complete repair. The excellent long-term results of corrective surgery concerning cardiac function and survival suggest that except for those rare cases where the operative risk is very high all adults with tetralogy of Fallot should undergo complete repair.

[Dilated cardiomyopathies and cytomegalovirus]. / Cardiomyopathies dilatées et cytomégalovirus.

Apparently primary dilated cardiomyopathy poses a difficult aetiological problem. There is epidemiological, biological and histological evidence that some of them are the long-term results of acute myocarditis especially due to Coksackie virus. In order to establish whether cytomegalovirus infection could also have the same consequences 67 cases of dilated cardiomyopathy were reviewed to look for inflammatory changes and CMV serology. The results indicate a possible link between acute CMV myocarditis and dilated cardiomyopathy (7 p. 100 of cases) but this is difficult to prove in the chronic stage of the disease.

[A case of autochtonous chronic Chagas cardiopathy in French Guiana]. / Un cas de cardiopathie chagasique chronique autochtone en Guyane Francaise.

After a brief review of Chagas' disease history in French Guiana, the authors report the first autochthonous case of Chagas' cardiopathy found in this country since 1956. The diagnostic suspected through epidemiological, clinical, electrocardiographical and echocardiographical data, was corroborated by serology and by the discovery of an apical aneurysm at post mortem examination of the heart.