HIV infection and immune system in genesis of coronary lesions.
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Biomedical subjects
Publications and source records attributed to G Dureau.
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Twenty anatomico-clinical cases of chronic cardiac rejection (accelerated coronary disease in heart transplant) consecutive to heart transplantation were studied with the view of obtaining detailed information on the anatomical features of coronary lesions, such as histopathological alterations, modalities of their diffusion to the 3 epicardial trunks and to distal intramyocardial branches, thrombotic complications and their consequences: massive (infarct) or disseminated myocardial ischaemia. The lesions observed were correlated with the corresponding coronary angiographic images, and an interpretation of the aetiopathological factors was attempted. Within a few months or years, the coronary lesions are found to progress towards very diffuse circumferential atherosclerous alterations where the plaques are clearly less individualized than in common atherosclerosis but thrombosis is frequent and multifocal in 50 percent of the cases. This produces a restrictive type of ischaemic cardiopathy which is painless since the heart is denervated, resulting in cardiac failure (11 cardiectomies for retransplantation, 9 autopsies) with coronary angiography tending to underestimate the importance of coronary damage. The most original aetiopathological factors seem to be arterial inflammation of immune origin, viral infections facilitated by immunosuppression and platelet hyperactivity, but their respective importance could not be accurately determined in this study.
Cyclosporine (Cy) binds to lipoproteins in plasma. In order to test if its pharmacokinetics would be modified when efficient lipid-lowering treatment is introduced, a study has been done of Cy pharmacokinetics and any interaction with the lipid-lowering agent fenofibrate in hyperlipidaemic long-term, survivors of heart transplantation. Fenofibrate 200 mg once daily significantly reduced blood lipids (cholesterol 6.5 vs 7.7 mmol/l; apoprotein B 1.2 vs 1.6 g/l) but did not modify mean whole blood Cy trough levels (113 before fenofibrate vs 103 ng.ml-1), Cmax (812 ng.ml-1 by RIA and 757 ng.ml-1 by HPLC before fenofibrate versus 865 and 741 respectively, during fenofibrate); tmax (1.6 and 1.7 h before fenofibrate versus 1.4 and 1.4 h respectively), and t1/2 (13.9 and 11.1 h versus 9.5 and 10.7 h). The only adverse effect was an increase in creatinine (157 vs 145 mmol/l). Further studies are needed to investigate the mechanism of Cy-fenofibrate nephrotoxicity and to evaluate the long-term efficiency and safety of fenofibrate after heart transplantation.
Accelerated coronary artery disease seems to be the main condition limiting long-term survival after heart transplantation. Ninety-one heart transplant recipients were compared with 94 nontransplanted coronary artery disease patients in an attempt to identify the factors responsible for the accelerated form of coronary artery disease occurring after heart transplantation. Among the parameters examined, heart transplant recipients exhibited a higher plasma level of insulin (8.5 +/- 0.5 versus 6.2 +/- 0.3 mIU/l, p = 0.002), a lower plasma level of vitamin E (14.8 +/- 0.4 versus 16.9 +/- 0.7 mg/l, p = 0.03), a higher platelet cholesterol-to-phospholipid ratio (8.9 +/- 0.3 versus 7.6 +/- 0.3, p = 0.007), and an increased response to ADP-induced platelet aggregation (for the first wave, 29.1 +/- 0.9% of maximal aggregation versus 25.1 +/- 1.0%, p = 0.002; for the second wave, 21.4 +/- 1.4% versus 15.9 +/- 1.1%, p = 0.002, after adjustment for hematocrit), but no untoward changes in the level of fibrinogen, plasminogen activator inhibitor-1, antithrombin III, or lipoprotein(a). In addition, platelet aggregation in patients who required retransplantation as a result of severe coronary artery disease was similar before and after retransplantation. This suggests that severe coronary artery disease is not the cause of platelet hyperaggregability. In multiple-regression analysis, ADP-induced platelet aggregation in heart transplant recipients was significantly positively related to blood glucose (r = 0.50, p less than 0.001) and inversely related to n-3 fatty acids from platelet phospholipids (r = 0.40, p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
The frequency and severity of atherosclerosis of the cardiac transplant make it an essential complication of cardiac transplantation. Coronary angiography is the usual diagnostic method but it has severe limitations. In order to evaluate other diagnostic methods coronary angiography and non-invasive techniques: echocardiography, exercise stress ECG, exercise radionuclide ejection fraction, stress Thallium scintigraphy, were performed practically simultaneously in 60 patients after cardiac transplantation. These non-invasive methods were said to be positive in the presence of, respectively, a segmental wall motion abnormality, ischaemic ST segment depression, absence of increased ejection fraction on exercise, reversible or irreversible myocardial hypofixation. Coronary angiography was considered as the reference procedure for distinction between "normal coronary circulation" (no angiographically detectable lesion) and "graft atherosclerosis" (at least one coronary stenosis irrespective of the severity and extension). None of the non-invasive methods had an adequate sensibility when compared with coronary angiography (echocardiography 0.27, exercise stress ECG 0.28, exercise radionuclide ejection fraction 0.64, myocardial scintigraphy 0.62) or negative predictive value (echocardiography 0.56, exercise stress ECG 0.58, exercise radionuclide ejection fraction 0.68, myocardial scintigraphy 0.66). This inadequacy of the non-invasive technique may be explained by the fact that they are more adapted to the diagnosis of myocardial ischaemia than that of coronary studies. In addition, the extent of the coronary lesions may have masked discordance between 2 segments by the global hypovascularisation. The results of this study indicate that the non-invasive methods studied cannot be recommended for diagnosis of atherosclerosis of cardiac transplants.
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In order to precise the pathologic aspects of coronary lesions observed in the accelerated coronary disease after heart transplantation, 15 cases of explanted hearts have been studied, and compared to the findings of previous coronarography. Histopathological aspects, modes of diffusion involving the three main coronaries and distal branches, thrombotic complications and their ischemic consequences showed that coronary lesions result in a few months or years to diffuse circumferential atheromatous like lesions. Localized lesions are less frequently encountered than in common atheromatous coronary disease, but multifocal thrombosis is frequent, found in 40% of the cases. This feature leads to ischemic cardiopathy expressed by cardiac failure, indolent because of the denervation of the heart. Correlations with coronarographies showed that this method underestimated the importance of coronary lesions, for which retransplantation represents the only hope. Risk factors include vascular immunological inflammation, viral infection enhanced by immunosuppression, increased platelet aggregation but we still ignore the respective importance of these factors at the present time.
The occurrence of squamous cell carcinomas in organ transplant recipients with warts represents a good model to study viral carcinogenesis. Most of the cases were reported in renal transplant recipients. We present the case of a heart transplant recipient in whom multiple common warts, preepitheliomatous keratoses, and squamous cell carcinomas developed. The warts began 4 years after the transplantation and the first carcinoma occurred 2 years after the warts, all the lesions being on sun-exposed areas. Histologic signs of human papillomavirus infection were seen in all premalignant and malignant lesions. Furthermore, human papillomavirus type 1 DNA was detected by in situ molecular hybridization within one of the carcinomas. Human papillomaviruses, along with other carcinogenic factors, play an important role in the development of carcinomas, and benign types could be implicated. Further studies are required to evaluate the frequency of cutaneous malignant neoplasms in heart transplant recipients as compared with renal transplant recipients.
Comparison of rat heart preservation by simple storage in a cardioplegic solution at 4 degrees C (6 hr for group I; 15 hr for group II) and by hypothermic low-flow perfusion of the same solution (0.3 ml min-1, 15 hr: group III) was performed by measuring biochemical and functional parameters and by collecting 31P-NMR spectroscopy data. When compared to control values, adenine nucleotide levels remained unchanged in group I hearts, while glycogen was 45% hydrolyzed and lactate level increased by 700%. Extension of heart immersion to 15 hr (group II) led to breakdown of ATP (-77%), of the sum of adenine nucleotides (-27%), and of glycogen (-77%), whereas lactate accumulation reached 900% of the control value. Functional recovery, measured at the end of a 60-min reperfusion was less than 10% in group II hearts when compared to group I hearts. This dramatic development was completely avoided by hypothermic low-flow perfusion (group III). 31P-NMR data showed that phosphocreatine was completely degraded in all groups of preserved hearts. Low-flow perfusion limited cellular acidosis. The ATP/Pi (Pi = inorganic phosphate) ratio calculated from NMR data was lower for group II hearts (0.04 +/- 0.01, n = 6) than for group I hearts (0.29 +/- 0.12; n = 6) or group III hearts (0.19 +/- 0.09; n = 6) and could constitute a convenient bioenergetic index to predict the capability of the heart to recover satisfactory contractility following a preservation period.
A case of right ventricular assistance required after emergency heart transplantation is reported. The patient was a 62 year-old man with terminal congestive heart failure due to ischaemic cardiomyopathy. Preoperatively, this patient had a cardiac index of 1.93 1.min-1.m-2, moderate pulmonary hypertension (mean Ppa: 34 mmHg) and pulmonary arteriolar resistances at 440 dyn.s.cm-5; clinical examination revealed pulmonary oedema, cardiac liver and oliguria with renal failure. Cardio-pulmonary bypass lasted 145 min, including 50 min of assistance after graft reperfusion. Despite postoperative dopamine and dobutamine treatment, oliguria and central venous pressure increased, and higher doses of catecholamines (adrenaline, noradrenaline) and pulmonary intraarterial prostaglandin E1 infusions were required. Despite these agents and haemofiltration, mechanical assistance was needed and a centrifugal pump set up. Diuresis and haemodynamic parameters improved. The patient was weaned from this assistance after 102 h. A satisfactory haemodynamic status was then maintained, but still required 1.4 micrograms.kg-1.min-1 noradrenaline and 0.02 microgram.kg-1.min-1 prostaglandin E1. Six days later, the patient was weaned from the ventilator, but he rapidly developed fatal aspergillus septicaemia. This case demonstrates that temporary mechanical assistance can be useful for treating right ventricular failure occurring after transplantation.
A series of 194 transplant subjects was followed-up by over 2,600 vectorcardiograms. Several cases of rejection were chosen among the most patent and best documented cases (eight cases of acute rejection and seven cases of chronic rejection) and 15 control cases where all tests, including the vectorcardiogram, had always remained negative. Two criteria of rejection were used, i.e. the amplitude of the left maximum QRS vector less than 1.10 mV and relative right spatial area greater than 35 per cent. By accumulating all traces for each patient, recorded during and outside the rejection phase, it was found that the mean of the individual means was 0.96 mV for the left amplitude in cases of rejection versus 1.74 mV in the control group, and 44 versus 22 per cent for the right area. The first trace which, on the curves showing the progress of each patient, was likely to signal acute or chronic rejection always had a left amplitude less than 1 mV (mean 0.89 mV) and a right area greater than 33 per cent (mean 45%). The first suspicious trace always preceded the detection of signs by echography or biopsy (except in one case where it occurred at the same time). The interval varied from 16 to 112 days in five cases of rejection assessed as acute, and from 63 to 600 days in seven cases of chronic rejection. There was no echographic control in two other cases, but death occurred 45 and 63 days after the first vectorcardiographic signs. The vectorcardiogram improves after recovery from acute rejection.(ABSTRACT TRUNCATED AT 250 WORDS)
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In a previous paper, we demonstrated that deep hypothermia in dogs provokes a release of a heparin-like factor. In the present study, we investigated some properties of this anticoagulant activity and compared it with exogenous heparin activity. The endogenous anticoagulant inhibited factors IIa and Xa; it was hydrolysed by heparinase and was AT III dependent. However, it differed from heparin in so far as it was adsorbed on cation exchange gel at neutral pH, its inhibition was decreased in the presence of neuraminidase, and it could not be neutralized with Polybrene or protamine. A release of heparan sulphate is suggested but remains to be demonstrated.
An enquiry by means of a questionnaire was conducted among 48 patients who had received a heart transplant, in order to evaluate their quality of life and their reinsertion into the french society. Health status, physical capacities, daily social and occupational activities and degree of satisfaction are analyzed. Eighty per cent of the patients considered themselves in excellent or good health; their Karnofsky's index, which globally assesses functional capacities, was 1.6, i.e. close to the normal value of 1 and to the results obtained in heart transplant recipients in the USA and in kidney transplant recipients; 61% of non-retired patients had resumed professional or learning activities. There were little changes in leisure activities. Matrimonial happiness was high, although sexual satisfaction was less complete than normally. Ninety-three per cent were satisfied with their life after transplantation.
The present study focuses on cell adhesion/differentiation and material stability of surfaces of the three carbon/ceramic composites implanted in intra-atrial position in dogs for 1 year. Before implantation their surface was characterized by scanning electron microscopy. After harvesting, the tissue proliferated on the blood interface was examined by histology, scanning, and transmission electron microscopy, wavelength dispersive and x-ray spectrometry, electrophoretic and enzymatic characterization of glycosaminoglycans (GAGs) which were compared to endocardiac tissue as control samples. One year after implantation, the pattern of GAGs in the newly developed tissue was characterized by: 1) a constant increase of the total GAGs present on all carbon composites, 2) a significant increase of dermatan sulfate (p less than 0.05), 3) a significant increase of chondroitin sulfate (p less than 0.05), 4) a significant decrease of heparan sulfate in Group 1, whereas this GAG fraction was increased in Groups 2 and 3. Cellular surface differentiation towards endothelial-like cells occurred in places particularly in groups 1 and 3, whereas only fibrous tissue was found covering the implants in Group 2. Fibroblastic cells with dense intracellular deposits, which produced emission of Si, Ca, and C energy as well as extracellular lipidic containing inclusions were observed. The macromolecular modifications were associated with 1) the absence of endothelial lining, 2) the migration of carbon and silicon particles, and 3) the occurrence of calcifications and lipidic inclusions. These results suggest that the relative smoothness of these materials could be responsible for the development of a tissue that did not adhere to the biomaterial, indicating that cell adhesion and functional differentiation are in intimal relationship with the physical-chemical structure of the material surface.
A new class of carbonaceous composites has been developed for cardiovascular devices. The aim of the present study, performed in dogs, was to test the immediate blood compatibility of these materials when inserted within the vascular bed. Biocompatibility studies were performed on vascular cylinders (6 mm i.d.) and intra-atrial implants. The specimens were examined sequentially by SEM at 10, 20, 30, 180 s and 10 min after re-establishment of the blood flow. Patency of the vascular cylinders was tested during the second and third postoperative month by Doppler ultrasound investigations; specimens were examined by light and electron microscopy (scanning and transmission) at 15, 60 and 110 d following implantation. As early as 10 s after re-establishment of the blood flow platelet adhesion and a limited fibrin mesh with few erythrocytes developed on the material. Platelet aggregates were only observed on intravenous implants. Except in the case of the intravenous insert, no thrombosis developed at the contact of intra-arterial or intracardiac implants. After 15 d it was completely covered by a fibrocellular layer (3-5 cells thick) consisting of large myofibroblasts with microfilaments, newly synthesized collagen and elastin. Endothelial-like cells developed and were completed 2 mnth after implantation. However, deposits present inside and outside the fibrocytic cells of the newly developed tissue were observed corresponding to carbon peaks as indicated by wavelength dispersive X-ray microanalysis.
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